WO2004031386A1 - Method of examining atopic dermatitis - Google Patents

Method of examining atopic dermatitis Download PDF

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Publication number
WO2004031386A1
WO2004031386A1 PCT/JP2003/009808 JP0309808W WO2004031386A1 WO 2004031386 A1 WO2004031386 A1 WO 2004031386A1 JP 0309808 W JP0309808 W JP 0309808W WO 2004031386 A1 WO2004031386 A1 WO 2004031386A1
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WIPO (PCT)
Prior art keywords
protein
gene
beta
receptor
group
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PCT/JP2003/009808
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French (fr)
Japanese (ja)
Inventor
Mikito Itoh
Kaoru Ogawa
Akira Shinagawa
Hajime Sudo
Hideoki Ogawa
Chisei Ra
Kouichi Mitsuishi
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Genox Research, Inc.
Juntendo University
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Application filed by Genox Research, Inc., Juntendo University filed Critical Genox Research, Inc.
Priority to AU2003252326A priority Critical patent/AU2003252326A1/en
Priority to JP2004541210A priority patent/JPWO2004031386A1/en
Publication of WO2004031386A1 publication Critical patent/WO2004031386A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A01K2267/0325—Animal model for autoimmune diseases

Definitions

  • the present invention relates to a method for testing atopic dermatitis.
  • Allergic diseases such as atopic dermatitis are considered to be multifactorial diseases. These diseases are caused by the interaction of the expression of many different genes, and the expression of these individual genes is affected by several environmental factors. For this reason, it is very difficult to elucidate the specific gene that causes a specific disease.
  • allergic diseases are thought to be related to the expression of genes having mutations or defects, or to overexpression or reduced expression of specific genes.
  • genes are involved in the pathogenesis and how external stimuli such as drugs alter gene expression.
  • allergens a method in which the immune response observed when a patient is actually contacted with an allergen is used to diagnose allergens (the latter).
  • tests include prick tests, scratch 'tests, patch' tests, intradermal reactions, or provocation tests. While these tests can directly diagnose a patient's allergic reaction, they can be described as tests involving invasive exposure of the subject to allergens.
  • test methods have been attempted to prove the involvement of allergic reactions regardless of the allergen.
  • a high serum IgE level may indicate that the patient has an allergic reaction.
  • the serum IgE value is information corresponding to the total amount of allergen-specific IgE. Although it is easy to determine the total amount of IgE regardless of the type of allergen, IgE may be low in patients with diseases such as non-atopic bronchitis asthma.
  • the present invention has been made in view of such a situation, and an object of the present invention is to provide a new index capable of testing for atopic dermatitis. Further departure Akira aims to provide a method for examining atopic dermatitis based on the index and a method for screening a candidate compound for a therapeutic agent for atopic dermatitis.
  • the present inventors have intensively studied to solve the above problems. That is, genes whose expression levels are different between the eruption in the same patient as the eruption of atopic dermatitis and the eruption in the atopic dermatitis patient and the skin of healthy subjects are identified. We clarified that we could find a new target for treatment of atopic dermatitis by clarifying its relationship with the atopic dermatitis response.
  • the present inventors developed a rash in the same patient as the eruption of atopic dermatitis and between the rash in the patient with atopic dermatitis and the skin of healthy subjects We searched for genes with different states.
  • the skin tissue of the subject was selected as a biological sample for comparing gene expression states. Skin tissue specimens that are actually inflamed are infiltrated with many lymphocytes, etc., which are important for the pathogenesis.Analysis of gene expression in the local skin is likely to elucidate the pathology of atopic dermatitis .
  • the present inventors compared the expression profile of a rash in the same atopic dermatitis patient as the rash in the same patient and genes expressed in the skin of healthy subjects using a gene chip. Genes with a two-fold or more expression fluctuation were selected, and the gene expression levels were measured. Then, it was confirmed that the expression of an indicator gene selected from the group described in any of the following a) to c) and c ′) and d ′) fluctuated. Furthermore, the present inventors analyzed the expression levels of these indicator genes in a mouse dermatitis model for mouse counterparts, and identified any of A) to D) as indicator genes related to mouse dermatitis. The indicator genes described in the group were selected.
  • the nucleotide sequences of the indicator genes described in any of a) to, c ') and d'), and A) to D) are known.
  • the functions of the proteins encoded by each of the indicator genes a) to) are described in the Reference section of Data 1 to Data 4 described later. It is stated in the sentence.
  • the functions of the proteins encoded by the c ′) and d ′) indicator genes are described in the papers described later in Data 7 and Data 8 in the Reference section.
  • the functions of the proteins encoded by the indicator genes of A) and B) are shown in Data 5 and Data 6
  • the functions of the proteins encoded by the indicator genes of C) and D) are shown in Data 13 and These are listed in the papers listed in the Reference section of Data 14 respectively.
  • the base sequences of psoriatic indicator genes i) to Lv) in the psoriasis test method according to the present invention and the amino acid sequence encoded by the indicator genes are known.
  • GenBank accession numbers of the known nucleotide sequences of the indicator genes of the present invention are as described in the following data 9 to data 12 (human).
  • the functions of the proteins encoded by each of the indicator genes i) to Lv) are described in the papers described in the Reference section of Data 9 to Data 12 described later. Although some of these genes have been reported to have a direct association with atopic dermatitis, many genes have not been reported to be associated with allergic disease.
  • each gene selected in this way We tried to compare with the expression level in.
  • a group of genes whose expression levels were specifically changed in patients with atopic dermatitis and psoriasis and a group of genes whose expression levels were commonly changed in both patients.
  • Genes that show changes specific to each disease can be expected to be useful as diagnostic indicators specific to each disease and target genes for treatment methods.
  • a group of genes whose expression levels change in both diseases in common can be expected to be useful as diagnostic indices common to skin inflammatory diseases and target genes for therapeutic methods.
  • the present inventors have proposed the diagnosis and diagnosis of atopic dermatitis or psoriasis by using the expression level of each indicator gene or the activity of the protein encoded by each indicator gene as an indicator.
  • the present inventors have found that it is possible to screen a therapeutic agent for the disease and complete the present invention.
  • the present invention relates to the following methods for examining atopic dermatitis and a method for screening a candidate compound for a therapeutic agent for atopic dermatitis.
  • a method for testing atopic dermatitis comprising the following steps (1) to (3), wherein the indicator gene is any one of the following a) to d), and any of c ') and d') A method which is any gene selected from the group described.
  • step (1) When the expression level measured in step (1) is the indicator gene described in a) or b), the expression level of the biological sample collected from the rash-free part of the same subject as a control The expression level of the indicator gene in the sample and, if the indicator gene is a gene described in any of c), c), d), and d '), the indicator gene in a biological sample of a healthy subject as a control Comparing with the expression level of
  • step (3) As a result of the comparison in step (2), when the indicator gene is the gene described in a), c) and c,), the expression level is higher than the control, W
  • RNase A family 5
  • RNase 4 deoxyribonuclease I-like 2 (DNAS1L2)
  • PCKl carbonic anhydrase isozyme VI
  • CA6 3-hydroxy-3-methy ⁇ glutary ⁇ coenzyme A synthase ⁇ arylacetamide de acetylase, ATPase, Cu ++ transporting, alpha polypeptide (ATP 7 A) tyrosinase (TYR), amylase, alpha 2B; pancreatic ⁇ CMP-N-acetylneuraminic acid hydroxylase
  • Aminomethy ⁇ transferase glycine cleavage system protein T
  • monoamine oxidase A Aldehyde dehydrogenase 5 family, member Al
  • CYTOCH ROME P450 CYTOCH ROME P450
  • SUBFAMILY IIIA POLYPEPTIDE 5 alcohol dehydrogen
  • syndecan 4 (amphiglycan, ryudocan) ⁇ progesterone receptor membrane component 2, peanut -like 1 (Drosophila) ⁇ type 1 angiotensin II receptor, variant 1-5, EphB6, proteolipid proteinic betacellul in ⁇ apMl (adipose most abundant gene transcript 1), proline rich 4 (lacrimal), prolactin-inducible protein ⁇ HZF9, skin-specific protein (xp32) N Crystall in, alph a B, retinol binding protein 4, Hepatocellular carcinoma antigen gene 5
  • DKFZP434G0310 hyperthetical protein
  • Purkinje cell protein 4 PCP 4
  • PCP 4 Purkinje cell protein 4
  • TRIM2 tripartite motif-containing 2
  • TIV metallothionein IV
  • N DKFZp586H2123, transmembrane 4 superfamily m ember 11 (oliposome)
  • DKFZp434A202 KIAA0471, KIAA0450, KIAA0624, KIA A0633, partial cds, KIAA0456, partial cds, DKFZp564D206, DKFZp586F1223, Clorf21, and DKFZp761F2014
  • a group of indicator genes consisting of the following genes whose expression level in the eruption area of atopic dermatitis patients is higher than that in healthy subjects: P13-kinase associated p85, pho sphoeno Ipyruvat e carboxykinase (PCK1 nucleotide pyrophosphates e, L-3-phosphoserine phosphatase ⁇ L-3-phosphoserine- phosphatase homolog ue, KIAA0369 / doublecortin and CaM kinase-like 1, tartrate— resistant aci d phosphatase type 5, pM5 protein ⁇ ADAM9 (a disintegrin and metalloprot einase domain 9 Ubiquitin-conjugating enzyme E2E 1, DKFZp586H2123, SP UVE (protease, serine, 23), squamous cell carcinoma antigen 2 (SCCA2 connexin 43 (GJA1, Cx43 plakophilin N desm
  • osphate receptor ⁇ MVP major vault protein
  • C0G5 component of oligome ric golgi complex 5
  • SIOO calcium- oinding protein A7 psoriasin 1
  • Ca N19 immunoglobulin lambda light chain ⁇ immunoglobulin heavy constant g amma 3
  • immunoglobulin kappa constant ⁇ major histocompatibility complex class II
  • DQ beta 1 immunoglobulin kappa constant ⁇ major histocompatibility complex
  • KIAA0440 RAB5, KIAA0400 / de ve 1 opment- and differentiation-enhancing factor 2
  • alternative activated macrophage specific CC chemokine 1 CC-chemokine MCP-4
  • small proline-rich protein IB cornerif in) ⁇ myosin he avy chain 12 (MY05A)
  • I and transcript release factor Mad4 homolog (Mad4), pituitary tumor-transforming protein 1, SMAD5, G0S2, eye 1 in B, Retinoblastoma 1, M130 antigenic extracellular variant (CD163), Z39IG, perilipin, apMl (adipose m ost abundant gene) transcript 1), DKFZp586J0323, KIAA1001 S KIAA0766, KIA A0101, DJ971N18.2 / KIAA1162, lung type-1 cell membrane-associated protein (Tla-- 2), metal lothi one in IV (MTIV), UTY (ubiquitously transcribed tet ratricopeptide) repeat gene, Y chromosome) Apg-1, HUNKI / MCAP S
  • FHL2 four and a half LIM domains 2
  • RBP4 retinol binding protein 4, plasma
  • An indicator gene group consisting of the following genes, the expression level of which is higher in the eruptions of patients with atby dermatitis than that of healthy subjects: transforming growth factor, beta receptor III (betaglycan, 300kD), BTF3 protein homologue, hemoglobin, alpha 1, hemoglobin, beta, alternative activated macrophage specific CC chemokine 1, Prolactin—Induced Protein, branched chain alph a-ketoacid dehydrogenase kinase ⁇ type I sigma receptor isoform 1, type I sigma receptor isoform 2, type I sigma receptor isoform 3, type I sig ma receptor isoform 4, type I sigma receptor isoform 5, ⁇ 0664 protein, FK506-binding protein IB isoform a, FK506-binding protein IB isoform b, lymphoid-; restricted membrane protein (LRMP), specific granule prote in (28 kDa) (SGP28), ATPas
  • An indicator gene group consisting of the following genes, whose expression level in the atopic region of atopic dermatitis patients is lower than that of healthy subjects: junD, c-jun protooncogene, c-fos, GOS / Fos— B, c-mycocogene ⁇ jun— B, ATF3 (activating trans cription factor 3), AREB6, ETR101 ⁇ ZFP36 (zinc finger protein 36), ets—2, EZF, MITF (microphthalmia- associated transcription factor) , EGRl (early growth response 1), EGR2 (early growth response 2), BTG2, excitation-3, Idl, Id2, Id3, TR3 (nuclear receptor subfamily 4, group A, member 1), NOT (nuclear receptor subfamily 4 , Group A, member 2), CL 100 / dual specif icit y phosphatase 1, cyclooxygenase-2 (hCox-2), cytochrome P
  • WAFl / cycl in-dependent kinase inhibitor 1A (p21, Cipl), GEM (GTP binding protein overexpressed in skeletal muse ⁇ e), G0S8 / RGS2 (regulator of G rotein signaling 2), A28-RGS14p, BL34 / regulator of G- protein signalling g 1, beta-2-adrenergi c receptor x major group rhinovirus receptor (HRV) / ICAM-1 (CD54), HB15 / CD83 S CD69, secreted epithelial tumor mucin antigen (MUC1) / CD227, SLC, GRO-beta , Amphiregulin (AR), heparin-binding EGF-lik e growth factor, KIM0508, DKFZp434A202 N DKFZp564F212, KIAA0924, RNU2 (RNA, U2 small nuclear), RIGUI / PERl (period homolog 1), metallo
  • An indicator gene group consisting of the following genes, whose expression level in the eruption area of atopic dermatitis patients is lower than that in healthy subjects: CL 100 I dual specifi city phosphatase 1, cyclooxygenase-2 ( hCox-2), Teel ⁇ receptor delta locus, chorionic gonadotropin beta subunit, dual specificity phosphatase 2, c-jun proto oncogene, c-fos, WAFl cycl in-dependent kinase inhibito r 1A (p21, Cipl), weel tyrosine kinase ⁇ jun-B, prostaglandin D2 synthas e, pleiotrophin, TR3 (nuclear receptor subfamily 4, group A, member 1), ATF3 (activating transcription factor 3>, tumor necrosis factor receptor super family, member 13B, H2B histone family , member H, keratin, hair, acidic, 3A, 37 kDa le
  • squamous cell carcinoma antigen ser ine protease inhibitor squamous cell carcinoma antigen 2 (SCCA2), mono ncyte / neirtrophi ⁇ e ⁇ astase inhibitor ⁇ alpha l ⁇ antitrypsin N elaf in inter leukin- / receptor N inter ⁇ eukin 4 receptor x platelet-derived endothelial cell growth factor ⁇ pre — B cell enhancing factor (PBEF) alternative activated macrophage specific CC chemokine 1, lactotransferrin ⁇ melanoma growth stimulatory activity (MGSA) / Gro alpha, psoriasin (S100A7), MR
  • the indicator genes of b) are cathepsin V, SERPINB7 (serine (or cysteine) protease inhibitor, clade B (ovalbumin), member 7), cytokeratin 15, de smin, extracellular matrix protein 2, KI0537, deoxyribonuclease I-lik e 2 (DNAS1L2) phosphoenolpyruvate carboxykinase (PCK1), 3-hydroxy-3-me thylglutaryl coenzyme A synthase ⁇ arylacetamide deacetylase N ATPase, Cu ++ transporting, alpha polypeptide (ATP7A) ⁇ tyrosinase (TYR), monoamine oxidase A , Aldehyde dehydrogenase 5 family, member Al, alcohol dehydrogenase 1A (class I), alpha polypeptide ⁇ alcohol dehydrogenase 1C (class
  • spermatocyte homolog sphingolipid delta 4 desaturase
  • alpha-2-glycoprotein 1 zinc N perilipin
  • lipoprot ein lipase ⁇ aldehyde dehydrogenase 3 family member A2
  • Hemoglobin alph a 1, alpha 2 chain, class I homeoprotein (H0XA9) promyelocytic leukemi a zinc finger protein (PLZF) ⁇ calcium channel, voltage-dependent, alpha
  • BTF3 protein homologue N general transcript ion factor I IF, polypeptide 2, 30 kDa, alternative activated macrophage sp ecific CC chemokine 1, complement component 1, q subcomponent, beta pol ypeptide s transforming growth factor, beta receptor III (betaglycan, 300 kD), branched chain alpha-ketoacid dehydrogenase kinase ⁇ ATPase, Ca ++ transporting, ubiquitous ⁇ tyrosinase- related protein 1, histidine ammon ia-lyase, androgen-; regulated short-chain dehydrogenase / reductase 1, gap junction protein, beta 3, 31kD (connexin 31), KI 0440, lymphoid-; res r icted membrane protein (LRMP), matrilysin (MP7), specific granule prot ein (28 kDa) (SGP28
  • ⁇ hemoglobin, alpha 1, sickle cell beta-globin, beta-globin (HBB), A-gamma globin s c arb oxype ti das e M, HCR (a-helix coi led-coil rod homologue) N nuclear receptor subfamily 1, group H, member 2, ESTs, Moderately similar to 2004399A chromosomal protein ⁇ any gene selected from runt-relat ed transcription factor ⁇ , and KI 0664 protein The method according to [1].
  • the indicator genes of d,) are Idl, BTG2, zinc finger protein 36, C3H typelike 1, EGR1 (early growth response 1), MIP-l-alpha, MCP1, tumor necros is factor receptor superfamily, member 13B , HB15 / CD83, CD95, FAS, CD69, T cell receptor delta locus, caspase 3, apoptosis—related cysteine protease, serine (or cysteine) proteinase inhibitor, clade I (neuroserpi n), member 1, SERPINE1, prostaglandin D2 synthase 21kDa (brain), choles terol 25-hydroxyiase, glutathione S-transferase M3 (brain), protein pho sphatase 5, catalytic subunit ⁇ phosphodiesterase 3B, regulator of G-pro tein signaling 16 , Heparin-binding EGF- ⁇ ike growth f actor N pleiotrophin,
  • the indicator genes of d,) are c-jun proto oncogene, jun-B, c-fos, G0S3 / Fos-B, c-myconcogene ⁇ AREB6, ATF3 (activating transcription factor 3), ETR101, ZFP36 (zinc finger protein 36>, GRO-beta, WAFl / cyclin-dependant kinase inhibitor 1A (p21, Cipl), interleukin 6 (interferon, beta 2), CL 100 / dual specificity phosphatase 1, cyclooxygenase-2 (hCox- 2), dua 1 specificity phosphatase 2, holocarboxylase synthetase ⁇ beta-2-adrenergic receptor ⁇ BL34 / regulator of G-protein signaling 1, GEM (GTP bind ing protein overexpressed in skeletal muscle), amphiregulin (AR), nucle ar receptor subfamily 4, group A, member 2, TR3 (nuclear
  • An atopic dermatitis test reagent comprising a polynucleotide containing the nucleotide sequence of the indicator gene or an oligonucleotide having a nucleotide sequence complementary to its complementary strand and having a length of at least 15 nucleotides. And a marker for atopic dermatitis, wherein the indicator gene is any one selected from the group described in a) to c) and c ′) and d ′) in [1].
  • An atopic dermatitis test reagent comprising an antibody that recognizes a peptide containing the amino acid sequence of the protein encoded by the indicator gene, wherein the indicator genes are a) to a) in [1], and A reagent for detecting atopic dermatitis, which is one of the genes selected from the group described in any of c ′) and d ′).
  • a method for screening for a therapeutic agent for tetopic dermatitis comprising the following steps, wherein the indicator gene is any of a;) to d), and any one of c ') and d') in [1].
  • a screening method which is any gene selected from the group described.
  • an atopy comprising a polynucleotide containing the nucleotide sequence of the indicator gene, or an oligonucleotide having a nucleotide sequence complementary to the complementary strand thereof and having a length of at least 15 nucleotides, and a cell expressing the indicator gene;
  • a kit which is any one of the genes selected from a) to c) and c ′) and d ′) according to [1].
  • An atopic dermatitis model animal comprising a transgenic non-human vertebrate with an increased expression level in the skin of an indicator gene or a gene functionally equivalent to the indicator gene, wherein the indicator gene is [1] A) a mouse animal selected from the group consisting of a),, and c, :), and any one of the groups described in A) or C) below.
  • An atopic dermatitis model animal comprising a transgenic non-human vertebrate with reduced expression intensity in the skin of an indicator gene or a gene functionally equivalent to the indicator gene, wherein the indicator gene is [1 A) a moral animal which is a gene selected from b), d), and d '), and any one of the groups described in B) or D) below.
  • a method for producing an animal model for allergic allergic dermatitis which comprises a step of administering the component according to any one of the following i) to iv) to a mouse.
  • Antisense or RA of a polynucleotide comprising a nucleotide sequence constituting any of the genes selected from the group of genes described in B) and D) in [20] or RAiv) B) and! )
  • An inducer for inducing allergic monodermatitis in mice comprising the ingredient according to any of i) to iv) in [22] as an active ingredient.
  • a method for screening a therapeutic agent for atopic dermatitis comprising the following steps, wherein the indicator gene is any one of a) to) and any one of c ') and d') in (1).
  • the screening method wherein the gene is a gene selected from the group or a gene functionally equivalent to the indicator gene.
  • a candidate compound is brought into contact with a cell into which a vector containing a transcription regulatory region of an indicator gene and a reporter gene expressed under the control of this transcription regulatory region has been introduced.
  • a method for screening for a therapeutic agent for atopic dermatitis comprising the following steps, wherein the indicator gene is any one of a) to) and c ′) and d ′) in (1). Screening method, which is a gene selected from the group or a gene functionally equivalent to the indicator gene.
  • atopic dermatitis comprising as an active ingredient a compound obtainable by the screening method according to any one of [14], [24], [25] and [26]; Remedy.
  • a therapeutic agent for atopic dermatitis containing the indicator gene or a part thereof as an active ingredient, wherein the indicator gene is selected from a), c) and c ') in [1].
  • a therapeutic agent for atopic dermatitis comprising, as an active ingredient, an antibody that recognizes a peptide containing an amino acid sequence of a protein encoded by an indicator gene, 2 7 ———
  • a therapeutic agent wherein the indicator gene is any one of the genes selected from the group described in any of a), c) s and c) in [1].
  • a therapeutic agent for atopic dermatitis comprising an indicator gene or a protein encoded by the indicator gene as an active ingredient, wherein the indicator gene is b), d) and d in [1].
  • a therapeutic agent which is any of the genes selected from the group described in any of).
  • the present invention provides an atopy comprising a step of administering a compound obtainable by the screening method described in any one of [14], [24] 2 [25] and [26].
  • the present invention relates to a method for treating atopic dermatitis.
  • the present invention also provides a pharmaceutical composition for treating atopic dermatitis, comprising a compound obtainable by the screening method according to any one of [14], [24], [25] and [26].
  • the present invention relates to a method for treating atopic dermatitis, comprising a step of administering the following component (i) or (ii).
  • the present invention relates to the use of the following component (i) or (ii) in the manufacture of a pharmaceutical composition for treating arthro- dermatitis.
  • the present invention relates to a method for treating atopic dermatitis, comprising a step of administering the following component (iii) or (iv).
  • the present invention relates to the use of the following component (iii) or (iv) in the manufacture of a pharmaceutical composition for treating atopic dermatitis.
  • the present invention also relates to the following psoriasis testing methods and screening methods for psoriatic therapeutic drug candidate compounds.
  • a psoriasis testing method comprising the following steps (1) to (3), wherein the indicator gene is any one selected from the group described in any of the following i) to iv): A method that is a gene.
  • step (1) If the expression level measured in step (1) is the gene described in i) or ii), the expression level measured in step (1) should be the same as the control. Comparing the expression level of the indicator gene in the sample with the expression level of the indicator gene in a biological sample of a healthy subject as a control, if the indicator gene is a gene described in ii i) or iv), Yo
  • Indicator genes consisting of the following genes, whose expression level in the rash area is higher in psoriatic patients than in the uncommon area: cellular retinoic acid binding protein 2, proteasome (prosome, macropain) activator subunit 2, interferon induced 6 -16 protein ⁇ heat shock 70kDa protein 4, flap structure-specific edonuclease 1, NME1, cycl in-dependent kinase inhibitor 3, ubiquitin-con jugating enzyme E2C, calreticulin s CDC2 gene, RAN, liver arginase (ARG 1), connexin 43 (GJAl, Cx43), interleukin 1 receptor antagonist ⁇ ATP-binding cassette, sub-family A (ABCl), member 12, M-phase phosphoprotein 6, creatine kinase, mitochondrial 1, edd4 binding protein 1, solute carrier family 7, member 5, acid phosphatase, prostate ⁇ plakophilin 1, UDP glycosyl transferase 1 f mily
  • arylsulfatase F potassium inwardly-rectifying channel, subfamily J, member 15, BUBl budding uninhibited by ben imidazoles 1 homo log beta (yeast) SPllO nuclear body protein isoform b, guanylate binding protein 1 (GBP1), GM2 gangli oside activator protein ⁇ complement factor B preproprotein ⁇ squalene ep oxidase, solute carrier family 5 (sodium / glucose cotransporter), member
  • N-myc (and STAT) interactor Stat2 tripartite motif-containing 22
  • kinesin-- ⁇ ike 6 kallikrein 10
  • N ribonucleotide reductase M2 polypeptide ⁇ chromosome 1 open reading frame 29
  • Sjogren syndrome antigen AI gamma-glutamyl hydrolase lymphocyte antigen 6 complex
  • locus E interle kin-activator kinase
  • N interferon-induced protein 44 lectin, galactosi de--binding, soluble, 3 binding protein s retinoblastoma binding protein 6, vipirin, interferon-- induced protein with tetratricopeptide repeats 4, SIOO calcium binding protein A12 (calgranulin C), bone marrow stroma ⁇ cell antigen 2, chromosome 20 open reading frame 1, aquaporin 3, cystatin A (stefin A), KIM0186, retinoblastoma-associated protein HEC, NSl-as sociated protein 1, topoisomerase (DNA) II alpha 170kDa N H2A histone fa
  • chemokine exodus-1 chemokine exodus-1, pituitary tumor-transforming 1, SCO cytochrome oxidase deficient homo log 2 (yeast)
  • N CDC28 protein kinase r egulatory subunit 2 kinesin-like 1, histidine ammonia-lyase, hypotheti cal protein FLJ10534, cyclin El, chromosome 1 open reading frame 34, ce llular retinoic acid binding protein 2, TTK protein kinase ⁇ acid phosphatase, prostate ⁇ interleukin 8 receptor beta (IL8RB) s RAB27A N MX2, thym idine kinase 1, interferon-inducible 56 Kd protein serum / glucocorticoi d regulated kinase ⁇ EphA2, nitric oxide synthase 2A, plasminogen activa tor, tissue type GM2 ganglioside activator protein ⁇ KIAA09
  • index gene group consisting of the following genes, whose expression level in the rash area is lower than that in the psoriasis area in psoriatic patients: actin, alpha 2, smooth muscle, aorta, actin, gamma 2, smooth muscle, enteric ⁇ cisplatin resistance associated ⁇ growth arrest-specific 6, insulin-like growth factor binding protein 6 (IGFBP6), insulin induced protein 1 (INSIG1), PDGF receptor beta-like tumor suppressor (PRLTS), R-ras, sarcospan (Kras oncogene- associated gene e), fibroblast growth factor (FGF) receptor-1, fibronectin 1 isoform 1 preproprotein % chromosome 21 open reading frame 25, seven in absentia h omolog 1 (Drosophi ⁇ a, fatty acid desaturase 1, fatty acid desaturase 2 ⁇ Rho-related BTB domain containing 3, matrilin 2, adipose specific 2, LI
  • ArgBP2a H0X2H mRNA from the Hox2 locus,: frizzled-related pr otein, G protein-coupled receptor, family C, group 5, member B, GABA-A receptor pi subunit N mesenchyme homeo box 2 (growth arrest-specific horn eo box), keratin 7, tumor-- associated calcium signal transducer 1, dioxin-inducible cytochrome P450 (CYP1B1), interleukin 1 receptor, type II, platelet / endothelial cell adhesion molecule (CD31antigen) GRB2- associa ted binding protein 2, mitogen inducible 2, transgelin N deleted in live r cancer 1, 8-oxoguanine DNA glycosylase, enolase 2, (gamma, neuronal) N pinin, desmosome associated protein N KIAA0367 gene s KIAA0280 gene, KIM 1053 protein.KIAA0729 protein, KIAA1467 protein, KIAA0716
  • DNA binding 4 (ID4), Beta-microseminoprotein isoform a (PSP94), isofor mb (PSP57), testicular inhibin beta-B ⁇ subunit x TM4SF3 (transmembrane 4 superfamily member 3), ITM2A (integral membrane protein 2A), claudin 8, syndecan 4 (amphiglycan, ryudocan) proteolipid protein 1, apMl (adipose most abundant gene transcript 1), prolactin-inducible protein ⁇ HZF9, skin-specific protein (xp32) Crystal 1 in, alpha B, Hepatocellular carcin oma antigen gene 520, Purkinje cell protein 4 (PCP4), 141H5, cyclin Dl, TRIM2 (tripartite motif - containing 2), metallothionein IV (MTIV), trans membrane 4 superfamily member 11 (plasmolipin), DKFZp434A202, KIAA0471, KIAA0
  • a group of indicator genes consisting of the following genes, whose expression level in the rash area of psoriatic patients is higher than that in healthy subjects: platelet factor 4 (PF4), actin, g amma 2, smooth muscle, enter ic interferon valpha, beta and omega) receptor 2, DNA topoisomerase I, CYP3A4, eye ⁇ in-dependent kinase 2, vascular r endothelial growth factor-D, ABL1, adducin 1 (alpha) isoform c , KLRC3, RAB2, l-acylglycerol-3-phosphate 0-acyltransf erase 2, tryptase, alpha ⁇ homolog of Yeast RRP4, MCM3, hemoglobin, delta, KI 1089, zinc finger protein 44 (KOX 7), arylacetamide deacetylase (esterase ) synuclein, gamma, elastase 2, neutrophil CYP3A5, FCGR3A (CD16), likely
  • An indicator gene group consisting of the following genes, whose expression level in the rash area of psoriasis patients is lower than that in healthy subjects: H2B histone family, member G, cho ⁇ inergic receptor, nicotinic, rieta polypeptide 4, related to the N term inus of tre, laminin, gamma 2 isoform b, interleukin 8, Kruppel-like factor 4 (gut) ⁇ Alstrom syndrome 1, occludin, c-ichi jun proto oncogene ⁇ jun -B, c-fos ⁇ G0s3 I Fos- B ⁇ c- myc oncogene ⁇ AREB6 ATF3 (activating transcript ion factor 3), ETR101, ZFP36 (zinc finger protein 36), GR0-beta, WAF1 I cycl in-dependent kinase inhibitor 1A (p21, Cipl), interleukin 6 (inter feron, beta 2),
  • HBpl7 heparin binding protein
  • breast cancer anti-estrogen resistance 3 heat shock 70kDa protein 2, ets variant gene 1, cAMP—dependent protein kinase subunit RII—beta, microtubule-associated protein, RP / EB family, member 2, ATP-binding cas sette, sub-family C (CFTR / MRP), member 3, transmembrane 4 superfamily ember 2, AXL receptor tyrosine inase s phospholamban ⁇ Fc fragment of Ig G binding protein ⁇ microsomal glutathione S— transferase 3, DEPP (decidu a ⁇ protein induced by progesterone ) N Arg / Abl-interacting protein ArgBP2a (ArgBP2a), H0X2H mRNA from the Hox2 locus, frizzled-related protein ⁇ G protein-coupled receptor, family C, group 5, member B, GABA—A receptor r pi subunit, mesenchyme homeo box 2 (growth arrest-specific homeo box)
  • the indicator genes of ii) are kallikreinl, cystatin E / M, tissue inhibitor of metalloproteinase 4, KIAA1775 (MT-protocadherin) N keratin 18, kera tin 19, smooth muscle myosin heavy chain 11, isoform SM2, sciellin (Sufi L) N KIAA0353 / desmuslin (intermediate filament protein) N calponinl N protein— tyrosine— phosphatase Dl, angiogenin (RNase A family, 5), Rase 4, carbonic anhydrase isozyme VI (CA6), amylase, alpna 2B ; pancreatic N CM ⁇
  • Aminomethyltransf erase (glycine cleavage system protein T), Cytochrome P450, subfamily IIIA, polypeptid e 5, alcohol dehydrogenase IB (class 1), beta polypeptide ⁇
  • FABP7 fatty acid binding protein 7
  • FABP4 Fatty acid binding protein 7
  • KIAA0273 / phytanoyl-CoA hydroxylase interacting protein ⁇ apol ipop rotein D, apolipoprotein E, hemoglobin, gamma A, gamma G, hemoglobin, beta, mammaglobin 1, mammaglobin 2, secretoglobin, family ID, member 2, delta sleep inducing peptide, immunoreactor s beta-catenin-interacting protein ICAT, GATA3, fork ead / winge d helix-like transcription factor 7 (FKHL7), Inhibitor of DNA binding 4 (ID4) N Beta-microseminoprotein isof orm a ( PSP94), isoform b (PSP57), testicular inhibin beta- B-subunit, TM4SF3 (transmembrane 4 superfamily member 3), ITM2A (integral membrane protein 2A), claudin 8, syndecan 4 (amphiglycan, ryudocan) s proteolipid
  • the indicator genes are platelet factor 4 (PF4), actin, gamma 2, smooth muscle, enteric ⁇ interferon (alpha, beta and omega) receptor 2, DNA topoisomerase I, CYP3A4, cyclin— dependent kinase 2, vascular endothial growth factor- D, ABL1, adducin 1 (alpha) isoform c, KLRC3, RAB2, 1 acylglycerol-3-phosphate 0-acy on transferase 2, tryptase, alpha, homolog of yeast RRP4, MCM3, hemoglobin, delta ⁇ KIAA1089, zinc finger protein W
  • the indicator genes of iii) are hemoglobin, alpha 1, sickle cell beta-glo bin, beta-globin (HBB), A-garama globin, carboxypeptidase M, HCR (a-heli x coiled- coil rod homologue) ), Nuclear receptor subfamily 1, group H, member 2, ESTs, Moderately similar to 2004399A chromosomal protein ⁇ runt-related transcription factor 1, and KIM0664 protein The described method.
  • the indicator genes of (iv) are H2B histone family, member G, cholinergic receptor, nicotinic, beta po ⁇ ypeptide 4, related to the N terminus of tr, laminin, gamma 2 isoform b, interleukin 8, Kruppel -The method according to [32], which is any gene selected from like factor 4 (gut), Alstrom syndrome 1, and occludin.
  • the indicator genes of iv) are C-jun proto oncogene, jun-B, c-fos, G0S3 I
  • a psoriasis test reagent comprising a polynucleotide containing the nucleotide sequence of the indicator gene or an oligonucleotide having a nucleotide sequence complementary to its complementary strand and having a length of at least 15 nucleotides,
  • a psoriasis test reagent comprising an antibody recognizing a peptide containing an amino acid sequence of a protein encoded by an indicator gene, wherein the indicator gene is any of i) to ⁇ ) in [32]. Any of the genes selected from the group described in
  • a method for screening a therapeutic agent for psoriasis comprising the following steps, wherein the indicator gene is any one of the genes selected from the group described in any one of i;) to iv) in [32]. Screening method. (1) contacting a candidate compound with cells expressing the indicator gene,
  • a psoriasis comprising a polynucleotide comprising the nucleotide sequence of the indicator gene, or an oligonucleotide having a nucleotide sequence complementary to the complementary strand thereof and having a length of at least 15 nucleotides, and cells expressing the indicator gene
  • the indicator gene is a kit selected from the group described in any one of i) to Lv) in [32].
  • a psoriatic model animal comprising a transgenic non-human vertebrate with an increased expression level in the skin of an indicator gene or a gene functionally equivalent to the indicator gene, wherein the indicator gene is as defined in [32]. i) a model animal which is any gene selected from the group described in group iii) group.
  • a psoriatic model animal comprising a transgenic non-human vertebrate with reduced expression intensity in the skin of an indicator gene or a gene functionally equivalent to the indicator gene, wherein the indicator gene is defined as ii in [32].
  • a method for screening a therapeutic agent for psoriasis comprising the following steps, wherein the indicator gene is any one selected from the group described in any one of i) to Lv) in [32]. Or a screening method that is a gene functionally equivalent to the indicator gene.
  • a method for screening a therapeutic agent for psoriasis comprising the following steps, wherein the indicator gene is any one of the genes selected from the group according to any of i) to iv) in (32), Or a screening method in which the gene is functionally equivalent to the indicator gene.
  • the indicator gene of the group i) or iii) is a compound that reduces the activity
  • the indicator gene of the group ii) or iv) is Selecting a compound that increases the activity
  • a treatment for psoriasis comprising as an active ingredient a compound obtainable by the screening method according to any one of [45], [53], and [54].
  • An indicator gene or a part thereof antisense DNA is contained as an active ingredient. 4 5: —111-J
  • a therapeutic agent for psoriasis wherein the indicator gene is any gene selected from the group according to any one of i) and iii) in [32].
  • a therapeutic agent for psoriasis comprising as an active ingredient an antibody that recognizes a peptide containing the amino acid sequence of the protein encoded by the indicator gene, wherein the indicator gene is (i) or (iii) in (32))
  • a therapeutic agent which is any gene selected from the group described in any of the above.
  • a therapeutic agent for psoriasis comprising an indicator gene or a protein encoded by the indicator gene as an active ingredient, wherein the indicator gene is selected from the group described in ii) or iv) in [32] Therapeutic agents that are any of the genes that were performed.
  • the present invention relates to a method for treating psoriasis, which comprises a step of administering a compound obtainable by the method according to any one of [45], [53], and [54]. .
  • the present invention also provides a use of a compound obtainable by the screening method of any one of (45), (53) and (54) in the manufacture of a pharmaceutical composition for treating psoriasis. About.
  • the present invention relates to a method for treating psoriasis, comprising a step of administering the following component (1) or (2).
  • the present invention relates to the use of the following component (1) or (2) in the manufacture of a pharmaceutical composition for treating psoriasis.
  • the present invention further relates to a method for treating psoriasis, comprising the step of administering the following component (3) or (4):
  • the present invention relates to the use of the following component (3) or (4) in the manufacture of a pharmaceutical composition for treating psoriasis.
  • an allergic disease is a general term for diseases associated with allergic reactions. More specifically, it can be defined as identifying an allergen, demonstrating a deep link between exposure to the allergen and the development of the lesion, and demonstrating an immunological mechanism for the lesion.
  • the immunological mechanism means that leukocyte cells show an immune response by allergen stimulation. Examples of allergens include mite antigens and pollen antigens.
  • Representative allergic diseases can include atopic dermatitis, bronchial asthma, allergic rhinitis, hay fever, or insect allergy.
  • Allergic diathesis is a genetic factor transmitted from parents to children with an allergic disease.
  • a familial allergic disease is also called an atopic disease, and the genetic factors that cause it are predisposed to atopy.
  • Atopic dermatitis is a generic term given to atopic diseases, particularly those associated with skin inflammatory conditions.
  • AD indicator gene a gene that can be used as an indicator of atopic dermatitis.
  • a protein consisting of the amino acid sequence encoded by the AD indicator gene is called an AD indicator protein.
  • the AD indicator gene is any one or more genes selected from the genes described in a) -d), c ') and d'), and A) -D) Is used as a term for
  • AD indicator gene of the present invention a gene selected from the following gene group is preferable as the gene of the group a) or b). These genes are included in the AD index gene group with a higher expression level in the rash area of atopic dermatitis patients than in the rash area of atopic dermatitis patients. It is a gene for which there was no significant difference in expression level between the rash and pustular areas of psoriatic patients. These AD indicator genes are unique in patients with atopic dermatitis It is a gene whose expression level is changed.
  • HME metalloproteinase
  • type IV collagenase N cathepsin Z precursor CT ⁇ L
  • CT ⁇ L disintegrin-protease
  • pro-cathepsin L major excreted protein MEP
  • skin collagenase s SPUVE protease
  • Proprotein convertase subti ⁇ isin / kexin typel
  • tissue inhibitor of metalloproteinases beta-migrating plasminogen activator inhibi tor I, IL-13Ral, IFN-beta 2a (IL-6), heparin-binding EGF-like growth Factor, GM-CSFR beta, interleukin 8 (IL8), MCP-1, EBIl-ligand chemokine, SLC, GRO-beta, monocyte chemotactic protein-2, CCR1, lymph node homing receptor I L-selectin, endothelial leukocyte adhesion molecule 1
  • LAPTn osomal--associated mult i transmembrane protein
  • KIM0296 serum amyloid Al
  • PA-F layer TYRO protein tyrosine kinase binding protein ⁇ fatty acid binding protein homologue
  • SEAP transme mbrane epithelial antigen of the prostate
  • aldehyde dehydrogenase 3 family member A2, Hemoglobin alpha 1, alpha 2 chain, class I homeoprotein (H0XA9), promyelocytic leukemia zinc f inge T protein (PLZF) N calcium channel, voltage—dependent, alpha 1H subunit s sodium channel, nonvoltage- gated 1, beta N LIGl (ortholog of mouse integral membrane glycoprotein G-1), WFSl (oltram syndrome 1), progestero ne receptor membrane component 2, peanut- like 1 (Drosophila) N type 1 an giotensin II receptor, variant 1-5, EphB6, betacellulin, proline rich 4 (lacrimal), retinol binding protein 4, DKFZP434G0310 (hypothetical pro tein), loricrin, DKFZp586H2123 KIM0624, DKFZp564D206, and DKFZp586F 1223
  • the AD indicator gene of the present invention a gene selected from the following gene group: The gene is preferred as a gene belonging to the group c ′) or d ′). These genes are included in the AD index gene group in which the expression level in the eruption area of atopic dermatitis patients is higher than that in healthy subjects compared to healthy subjects. No significant difference was found in the expression level in the comparison between the rash-free area and healthy subjects. These AD indicator genes are also genes whose expression levels are specifically changed in patients with atopic dermatitis.
  • E fena BTF3 protein homologue, general transcription factor I IF, polypeptide 2, 30kDa, alternative activated macro phage specific CC chemokine 1, complement component 1, q subcomponent, beta polypeptide ⁇ transforming growth factor, beta receptor III (betagl yean, 300kD), branched chain alpha-ketoacid dehydrogenase kinase N ATPase, Ca ++ transporting, ubiquitous ⁇ tyrosinase-related protein 1, histidi ne ammonia- ⁇ yase, androgen— regulated short-chain dehydrogenase / reductas e 1, gap junction protein, beta 3, 31kD (connexin 31), KI 0440, lympho id-restricted membrane protein (LRMP), matrilysin (MMP7), specific gran ule protein (28 kDa) (SGP28), type I sigma receptor % FK506 binding protein
  • a gene that can be used as an indicator of psoriasis is referred to as a psoriasis indicator gene.
  • a protein consisting of an amino acid sequence encoded by a psoriasis indicator gene is called a psoriasis indicator protein.
  • the psoriasis indicator gene is used as a term indicating any one or more arbitrary genes selected from the genes described in i) to iv).
  • an indicator gene or an indicator protein it is used as a term including both the AD indicator gene (and the AD indicator protein) and the psoriasis indicator gene (psoriasis indicator protein).
  • genes selected from the following gene groups are preferable as the genes of the above-mentioned group i) or group ii). These genes are included in the psoriatic index gene group, i. This gene did not show a significant difference in the expression level between the skin area and the eruption area of the patient. These psoriatic index genes are specifically expressed in psoriatic patients Is the gene that is changing.
  • cellular retinoic acid binding protein 2 proteasome (prosome, macropain) activator subunit 2, interferon in prised 6-16 protein
  • N heat shock 70kDa protein 4 flap structure-specific endonuclease 1, NME1 , Eye 1 in-dependent kinase inhibitor 3, ubiquitin-conjugating enzyme E2C, calreticulin ⁇ CDC2 gene, RAN, liver arginase (AR Gl) ⁇ connexin 43 (GJAl, Cx43) ⁇ interleukin 1 receptor antagonist ⁇ ATP-b inding cassette, sub-family A (ABCl), member 12, M-phase phosphoprotein
  • arylsulfatase F potassium inwardly-rectifying channel, subfamily J, member 15, BUBl budding uninnibited by benz imidazoles 1 homolog beta (yeast)
  • N SPllO nuclear body protein isoform b Guanylate binding protein 1 (GBP1), GM2 gangli oside activator protein s complement factor B preproprotein N squalene ep oxidase ⁇ solute carrier family 5 (sodium / glucose cotransporter), member
  • actin alpha 2, smooth muscle, aorta actin, gamma 2 smooth muscle, enteric ⁇ cisplatin resistance associated ⁇ growth arrest—specific 6 insulin-like growt factor binding protein 6 (IGFBP6), insulin induced protein 1 (INSIG1), PDGF receptor beta--like tumor suppressor (PRLTS), R--ras sarcospan (Kras oncogene-associated gene), fibroblast growth factor (FGF) receptor-1 f ibronectin 1 is of or in 1 preproprotein ⁇ chromosome 21 open reading frame 25 seven in absentia h omolog 1 (Drosophila) x fatty acid desaturase 1 fatty acid desaturase 2 5 3: — one one-i
  • Rho-related BTB domain containing 3, matri in 2, adipose specific 2, LI M protein ⁇ LIM domain binding 2 / CLIM1 myosin light chain kinase (MLC K), myosin, light polypeptide 9, regulatory ⁇ tropomyosin 1 (alpha), cys teine-rich protein 1 (intestinal), reversion- inducing-cysteine-rich pro tein with kazal motifs, amine oxidase, copper containing 3 (vascular ad hesion protein 1), cytochrome c oxidase subunit Vila polypeptide 1 (mus cle), chemokine ( C-C motif) ligand 14, ocular development-associated gene, ephrin—B2, Na, K-ATPase subunit alpha 2 (ATP1A2), ATPase, Ca ++ trans porting, ubiquitous, aquaporin 9, pleiotrophin ⁇ cadherin 19, type 2, WN T
  • ArgBP2a H0X2H mRNA from the Hox2 locus, frizzled-- related pr otein, G protein-coupled receptor, family C, group 5, member B, GABA-A receptor pi subunit N mesenchyme homeo box 2 (growth arrest-specific hom eo box) keratin 7, tumor-associated calcium signal transducer 1, dioxi n-induci le cytochrome P450 (CYP1B1 interleukin 1 receptor, type II, platelet / endothelial cell adhesion molecule (CD31 antigen) s GRB2— associa ted binding protein 2, mitogen inducible 2, transgelin s deleted in live r cancer 1, 8-oxoguanine DNA glycosylase, enolase 2, (gamma, neuronal) pinin, desmosome associated protein ⁇ KIAA0367 gene, KIAA0280 gene, KIM 1053 protein ⁇ KIAA0729 protein ⁇ KIAA1467 protein
  • genes selected from the following gene groups are preferable as the genes of the group iii) or iv). These genes have a higher expression level in the eruption area of psoriasis patients than in healthy subjects.
  • These psoriasis indicator genes are also genes whose expression levels are specifically changed in psoriatic patients.
  • Preferred genes as group genes: H2B histone family, member G, cholin ergic receptor, nicotinic, beta polypeptide 4, related to the N terminus of tre, ⁇ aminin, gamma 2 isoform b, interleukin 8, K upp el- like factor 4 (gut), Al strom syndrome 1, and occludin
  • the nucleotide sequence of the indicator gene and the amino acid sequence encoded by the nucleotide sequence in the present invention are known.
  • GenBank accession number for obtaining the sequence data of the AD indicator gene is summarized below along with the name of the indicator gene.
  • the method for detecting an allergic monogenic disease of the present invention measures the expression level of each indicator gene in a biological sample of a subject, and when the indicator gene is a gene described in a) or b) above, The expression level of the indicator gene in a biological sample collected from the eruption of the same subject as a control, and the indicator gene is a gene described in any of d), c,) and) above.
  • the method includes a step of comparing the expression level of the indicator gene in a biological sample of a healthy subject as a control. If the indicator gene is a gene described in any of the above a),, and c '), the subject is determined to be atopic dermatitis if the expression level is higher than that of the control. And the indicator gene is above! In the case of a gene described in any of)), d) and d '), a subject is judged to be atopic dermatitis if the expression level is lower than that of the control.
  • the psoriasis detection method of the present invention ⁇ Well, by measuring the expression level of each indicator gene in a biological sample of a subject, and determining that the indicator gene is As a control, the expression level of the indicator gene in a biological sample collected from the eruption of the same subject, and if the indicator gene is a gene described in iii) or iv) above, a healthy control If the indicator gene is the gene described in i) or iii) above, test if the expression level is higher than that of the control. Are determined to have psoriasis It is. If the indicator gene is a gene described in ii) or iv) above, the subject is determined to be psoriasis when the expression level is lower than that in the control.
  • a standard value is usually set based on the expression level of the indicator gene in a healthy person, for example. Based on this standard value, for example, the range of ⁇ 2 S.D. Techniques for setting a standard value and an allowable range based on a measured value of an indicator gene are known.
  • the standard value of the rash-free area in the patient can be determined by measuring the expression level of the indicator gene in the rash-free area in advance. After setting the standard value, only the expression level of the rash area is measured, and the test method of the present invention can be carried out based on a comparison with a standard value of the rash area of the patient determined in advance.
  • the test is performed if the expression level is higher than the allowable range compared to the control. Are determined to have atopic dermatitis.
  • the indicator gene in the subject is a gene described in any of b), d) and d ') above, if the expression level is lower than the allowable range compared to the control, However, the subject is determined to have atopic dermatitis. If the expression level of the indicator gene is within the acceptable range, it is expected that the possibility of atopic dermatitis is low.
  • the subject is determined to have psoriasis if the expression level is higher than the acceptable level compared to the control. You. Similarly, if the indicator gene in the subject is the gene described in ii) or iv) above, the subject has psoriasis if the expression level is lower than the acceptable level compared to the control Is determined. If the expression level of the indicator gene is within the allowable range, the possibility of psoriasis is expected to be low.
  • the expression level of the indicator gene includes the transcription of the indicator gene into mRNA and the translation into a protein. Therefore, the detection of atopic dermatitis according to the present invention
  • the method is performed based on a comparison of the expression intensity of mRM corresponding to the indicator gene or the expression level of the protein encoded by the indicator gene.
  • the expression level of the indicator gene in the examination for atopic dermatitis or psoriasis in this effort can be measured according to a known gene analysis method. Specifically, for example, a hybridization technique using a nucleic acid that hybridizes to this gene as a probe or a gene amplification technique using DNA that hybridizes to the indicator gene of the present invention as a primer can be used. .
  • Probes or primers used for the test of the present invention can be designed based on the nucleotide sequence of the indicator gene.
  • the nucleotide sequence of the indicator gene and the amino acid sequence encoded by the indicator gene are known. GenBank Akuseshiyon number of nucleotide sequences of the marker genes of the present invention, the following data 1 data 4 Contact Yopi data 7 Data 1 2 (human), and the data 5 to data 6 and the data 1 3 - data 1 4 (Mouse ).
  • the nucleotide sequence of a part of the indicator gene of the present invention and the amino acid sequence encoded by the nucleotide sequence are shown in the following SEQ ID NOs. 'In general, genes in higher animals are frequently associated with polymorphisms.
  • the indicator gene includes not only human but also homologs of other species. Therefore, an indicator gene in a species other than human refers to a homologue of the indicator gene specific to the species or an exogenous indicator gene introduced into the individual, unless otherwise specified.
  • a homologue of a human indicator gene refers to a human indicator gene that can hybridize under stringent conditions using a human indicator gene as a probe.
  • Stringent conditions generally indicate the following conditions. That is, the cells are hybridized at 4 ⁇ SSC at 65 ° C., and washed at 65 ° C. for 1 hour using 0.1 ⁇ SSC.
  • the temperature conditions for hybridization and washing which greatly affect the stringency, can be adjusted according to the melting temperature (Tm). Varies depending on the ratio of constituent bases to the hybridized base pairs and the composition of the hybridization solution (salt concentration, sodium formamide-dodecyl sulfate concentration). Therefore, those skilled in the art can experimentally or empirically set conditions that give equivalent stringency in consideration of these conditions.
  • a polynucleotide comprising the nucleotide sequence of the indicator gene or a polynucleotide containing at least 15 nucleotides complementary to a complementary strand thereof can be used.
  • the “complementary strand” refers to one strand of the double-stranded DNA consisting of A: T (U for RNA) and G: C base pairs, relative to the other strand.
  • the term ⁇ complementary '' is not limited to the case where the sequence is completely complementary to at least 15 contiguous nucleotide regions, but is at least 70%, preferably at least 80%, more preferably 90%, and even more preferably 95%. It suffices to have at least the homology on the base sequence of at least%. Nucleotide sequence homology can be determined by an algorithm such as BLAST.
  • Such a polynucleotide can be used as a probe for detecting the indicator gene and as a primer for amplifying the indicator gene.
  • a primer usually, 15Bp ⁇ 100bp, preferably having a chain length of 15bp ⁇ 35b P.
  • a DNA having at least a part or all of the sequence of the indicator gene (or its complementary strand) and having a chain length of at least 15 bp is used.
  • the 3 ′ region must be complementary, but a restriction enzyme recognition sequence tag or the like can be added to the 5 ′ region.
  • the “polynucleotide” in the present invention can be DNA or RNA. These polynucleotides may be synthetic or natural.
  • the probe DNA used for hybridization is usually labeled.
  • the labeling method for example, the following methods can be shown.
  • oligonucleotide means a polynucleotide having a relatively low degree of polymerization. Oligonucleotides are included in polynucleotides.
  • the test for atopic dermatitis using the hybridization technique can be performed using, for example, a Northern hybridization method, a dot plot method, a method using a DNA microarray, and the like.
  • gene amplification techniques such as the RT-PCR method can be used.
  • the expression of the indicator gene of the present invention can be analyzed more quantitatively by using the PCR amplification monitoring method in the gene amplification process.
  • probes that are labeled with different fluorescent dyes that cancel each other's fluorescence on both ends are used to hybridize to the detection target (reverse transcript of DNA or RNA).
  • the number of copies of the target in the target sample is determined based on the number of linear cycles of PCR amplification by simultaneously measuring a standard sample with a clear copy number for the target (Holland, PM et al., 1991, Proc. Natl. Acad. Sci. USA 88: 7276-7280; Livak, KJ et al., 1995, PCR Methods and Applications 4 (6): 357-362; Heid, CA et al., Genome Research 6: 986. -994; Gibson, E, MU et al., 1996, Genome Research 6: 995-1001).
  • ABI PRISM7700 Applied Biosystems 3 ⁇ 4h
  • the method for testing atopic dermatitis or psoriasis of the present invention can also be performed by detecting a protein encoded by an indicator gene.
  • a test method for example, a Western blotting method, an immunoprecipitation method, an ELISA method, or the like using an antibody that binds to each indicator protein can be used.
  • Antibodies that bind to the indicator protein used for this detection can be obtained using techniques well known to those skilled in the art.
  • the antibody used in the present invention can be a polyclonal antibody or a monoclonal antibody (Milstein C, et al., 1983, Nature 305 (5934): 537-40).
  • a polyclonal antibody against an indicator protein is obtained by extracting blood of a mammal sensitized with an antigen and separating serum from the blood by a known method.
  • serum containing the polyclonal antibody can be used.
  • a fraction containing a polyclonal antibody can be further isolated from the serum.
  • immunocytes are removed from a mammal sensitized with the above antigen and myeloma cells or the like are extracted. ⁇
  • the hybridoma thus obtained is cloned, and the antibody is recovered from the culture to obtain a monoclonal antibody.
  • antibodies may be appropriately labeled and used for detection of the indicator protein.
  • a substance that specifically binds to the antibody for example, protein A or protein G can be labeled and detected indirectly.
  • a specific detection method for example, an ELISA method can be mentioned.
  • a protein or a partial peptide thereof used as an antigen can be obtained by, for example, incorporating an indicator gene or a part thereof into an expression vector, introducing this into an appropriate host cell, preparing a transformant, and culturing the transformant. Then, the recombinant protein is expressed, and the expressed recombinant protein can be obtained by purifying it from a culture or a culture supernatant.
  • an oligopeptide consisting of the amino acid sequence encoded by the gene or a partial amino acid sequence of the amino acid sequence encoded by the full-length cDNA can be chemically synthesized and used as an immunogen.
  • allergic diseases or psoriasis can be tested using not only the expression level of the indicator gene but also the activity of the indicator protein in a biological sample as an indicator.
  • the activity of the indicator protein refers to the biological activity of the protein.
  • a general method for measuring the activity of each protein will be described.
  • Protease inhibitor is copolymerized with a protease substrate such as gelatin.
  • a protease substrate such as gelatin.
  • the gel is stained with bear sieve brilliant blue R250, and the protease inhibitor swimming activity is stained, that is, the gelatin is not degraded, so that the protease inhibitor activity can be evaluated.
  • the transcription factor is incubated with double-stranded oligo DNA containing the target sequence of the transcription factor labeled with 32 P or the like at room temperature to bind.
  • the sample after the incubation is subjected to electrophoresis on a non-denaturing polyacrylamide gel containing no SDS, and the mobility of the labeled oligo! NA is evaluated using the radioactivity of 32 P as an index. If the transcription factor has an activity to bind to oligo DNA, the mobility of the labeled oligo DM becomes slow and shifts to higher molecular weight.
  • the binding specificity for the target sequence can be confirmed by inhibiting the binding between the transcription factor and the labeled oligo DNA by an excessive amount of unlabeled double-stranded oligo DNA.
  • a reporter gene expression vector is an expression vector in which a reporter gene such as chloramphenicol acetyltransferase (CAT) is linked downstream of its target sequence.
  • CAT chloramphenicol acetyltransferase
  • a transcription factor whose activity is to be evaluated can be expressed by a transcription factor expression vector in which a transcription factor gene is linked downstream, such as a human cytomegalovirus (CMV) response gene promoter.
  • CMV human cytomegalovirus
  • [Kinase] Buffer containing kinases myelin basic protein as substrate (. 20 mM HEPES, p H7 5, 10 mM MgCl 2, 2 niM MnCl 2, 2 mM dithiothreitol, and 25 ATP) was added to warm to further [gamma - 32 P ] Add ATP and incubate at 37 ° C for 10 minutes. After 10 minutes, stop the reaction with Lae deer buffer solution, subject the reaction solution to SDS polyacrylamide gel electrophoresis, dry the gel after swimming, and detect the radioactivity of phosphorylated myelin basic protein on X-ray film I do.
  • phosphatase to a buffer solution (25 mM MES, H 5.5, 1.6 mM dithiothreitol, 10 mM pNPP) containing p-nitrophenyl phosphate (pNPP) as a substrate, and incubate at 37 ° C for 30 minutes. After 30 minutes, the reaction is stopped by adding IN NaOH, and the absorbance at 405 nm resulting from the hydrolysis of pNPP is measured.
  • a buffer solution 25 mM MES, H 5.5, 1.6 mM dithiothreitol, 10 mM pNPP
  • pNPP p-nitrophenyl phosphate
  • the cells in which the chemokine receptor is forcibly expressed are suspended in Hank's balanced salt solution containing a calcium-sensitive fluorescent dye fura-2, and stimulated with a chemokine.
  • the increase in intracellular calcium concentration caused by chemokine stimulation is measured with a fluorescence detector such as LS50B (PerkinElmer).
  • Cells that express the cytokine receptor are stimulated with cytokines, and the cell proliferation caused by the stimulation is assessed by thymidine incorporation.
  • activation of a transcription factor located downstream of a cytokine receptor by cytokine stimulation can be evaluated by expression of a reporter gene such as luciferase.
  • a patch clamp that attaches a membrane containing an ion channel to the tip of the glass pipe of im 2 and gives a potential difference outside the pipe to measure the current passing through the channel at that time. It can be evaluated by the method.
  • Cells expressing the adhesion molecule on the cell surface are incubated on a plate coated with the ligand, and the number of adhered cells is evaluated.
  • the skin tissue of the subject is used as a sample.
  • the collection of skin tissue samples is somewhat painful to the subject.
  • skin tissue can be easily collected and is useful as a diagnostic material.
  • Skin tissue can be collected, for example, as follows. That is, the sampling site is first anesthetized with a local anesthetic. After pulling the skin around the biopsy site to make it slack-free, embed the punch in the skin and rotate it to insert the tissue of the specimen into the punch. Pull out the punch and collect the cut skin inside the punch.
  • a punch is a hollow skin tissue sampling device. For example, a device that can collect skin tissue with a diameter of 3 mm It is commonly used.
  • the skin tissue anatomically includes the epidermis and the dermis.
  • Skin tissue can include non-skin cells found in skin tissue, such as lymphocytes, Langerhans cells, or mast cells, as well as cells specific to the skin. Cells collected together with these skin cells are also included in skin tissue samples.
  • a skin tissue sample from the rash is used to determine the expression level of the indicator gene in the rash.
  • the rash is the skin that forms the acute lesion.
  • acute lesions can be determined according to the diagnostic criteria reported in Japanese Dermatological Association 104: 1210 (1994). Specifically, for example, the following clinical findings are used as indicators of acute lesions.
  • Acute lesions erythema, wet erythema, papules, serous papules, scales, crusts
  • a skin tissue sample of the rash-free area is used.
  • the eruption in the patient is the skin at a site not accompanied by the above lesion.
  • the skin tissue of a healthy subject is used.
  • the healthy subject in the present invention refers to a human who clearly has no disease to be diagnosed. That is, in testing for allergic diseases, humans without allergic diseases are healthy subjects.
  • a person without psoriasis is a healthy subject. A healthy person is allowed to have a disease other than the disease to be diagnosed.
  • preferred healthy individuals are those who have neither allergic disease nor psoriasis.
  • the skin tissue can be collected by the same method as the collection of the patient's skin tissue.
  • skin from different sites can be used for comparison. Wear.
  • the collection of skin tissue samples is easy, simple examinations at medical sites are possible.
  • it can be prepared by the method shown in Examples. If the prepared skin tissue is lysed into lysate, it can be used as a sample for immunological measurement of the indicator protein.
  • a lysate is prepared from the above biological sample, it can be used as a sample for immunological measurement of the indicator protein.
  • mRNA is extracted from this lysate, it can be used as a sample for measuring mRNA corresponding to the indicator gene. It is convenient to use commercially available kits for extracting lysates or mRNA from biological samples.
  • the indicator protein is secreted into the blood, the expression level of the gene encoding the protein can be measured by measuring the amount of the target protein contained in a body fluid sample such as blood or serum of the subject. Comparison is possible.
  • the above sample can be diluted with a buffer or the like, if necessary, and used in the method of the present invention.
  • the measured value of the expression level of the indicator gene in the present invention can be corrected by a known method. With the correction, changes in the expression level of the gene in the cells can be compared.
  • the measurement value is corrected based on the measurement value of the expression level of a marker gene (for example, a housekeeping gene) whose expression level does not fluctuate greatly in each cell in the biological sample. This is done by correcting. Examples of the gene whose expression level does not fluctuate greatly include -actin, GAPDH and the like.
  • the present invention provides a reagent for the test method of the present invention. That is, the present invention relates to a test reagent for atopic dermatitis, comprising a polynucleotide containing a base sequence of an indicator gene or an oligonucleotide having a base sequence complementary to a complementary strand thereof and having a length of at least 15 bases. . Alternatively, the present invention relates to a reagent for testing atopic dermatitis, comprising an antibody that recognizes an indicator protein. Book Oligonucleotides and antibodies constituting the reagent of the present invention can be bound with an appropriate label according to the assay format.
  • the oligonucleotide or antibody constituting the reagent of the present invention can be immobilized on a suitable support according to the Atsey format.
  • the reagent of the present invention can be used as a test kit by combining the oligonucleotide or the antibody with additional components necessary for testing and storage. Additional components that can make up the kit are shown below. These components can be pre-mixed if necessary. If necessary, preservatives and preservatives can be added to each element.
  • the expression level of the AD indicator gene in the present invention is expressed in each skin tissue in a rash-free area in the same patient as the rash in an atopic dermatitis patient, or in a comparison between a rash-free area in an atopic dermatitis patient and a healthy subject. Was confirmed. Therefore, atopic dermatitis can be tested using the expression level of the AD indicator gene as an indicator.
  • the test for atopic dermatitis in the present invention includes, for example, the following tests. Even if a patient can not determine atopic dermatitis by general examination while showing symptoms that atopic dermatitis is suspected, if the test based on the present invention is performed, whether the patient is a patient with atopic dermatitis Can be easily determined.
  • the AD indicator gene when the AD indicator gene is a gene described in any of a), c), and c ') in a patient exhibiting symptoms of suspected atopic dermatitis, the AD indicator gene Increased expression indicates that the cause of the condition is likely to be atopic dermatitis.
  • patients with symptoms of suspected atopic dermatitis When the AD indicator gene is a gene described in any of b), d), and d '), a decrease in the expression of the AD indicator gene is caused by atopic dermatitis, which is also caused by the symptoms. It indicates that there is a high possibility.
  • tests can be performed to determine if atopic dermatitis is improving. In other words, it is useful for judging the therapeutic effect on atopic dermatitis.
  • the AD indicator gene is a gene described in any of a),, and c
  • the increase in expression of the AD indicator gene is This indicates that dermatitis is likely to be more advanced.
  • the decrease in the expression of the AD indicator gene is also This indicates that atopic dermatitis is likely to be more advanced.
  • the severity of atopic dermatitis can be determined based on the difference in expression level. That is, when the AD indicator gene is a gene described in any of a), c)), the degree of increase in the expression of the AD indicator gene correlates with the severity of atopic dermatitis. Alternatively, when the AD indicator gene is any of the genes listed in b), d) and d '), the degree of decrease in the expression of the AD indicator gene correlates with the severity of atopic dermatitis I do.
  • the expression level of the psoriatic index gene in the present invention is expressed in each skin tissue in comparison between the eruption area of the same patient as the rash area of a psoriasis patient or the rash area of an acute psoriasis patient and a healthy subject. Fluctuation was confirmed. Therefore, psoriasis can be detected using the expression level of the psoriasis indicator gene as an indicator.
  • the test for psoriasis in the present invention includes, for example, the following tests. Even if a patient cannot be determined to be psoriasis by a general test while showing symptoms suspected of psoriasis, the test according to the present invention can easily determine whether or not the patient is a psoriasis patient. . More specifically, in patients with symptoms suspected of psoriasis, P
  • the psoriasis indicator gene is a gene described in i) or iii
  • an increased expression of the psoriasis indicator gene indicates that the cause of the symptom is likely to be psoriasis.
  • the psoriatic index gene is a gene described in ii) or iv) in a patient who exhibits symptoms suspected of psoriasis, a decrease in the expression of the psoriasis index gene is also caused by psoriasis. It indicates that the possibility is high.
  • tests can be done to determine whether psoriasis is improving. In other words, it is useful for determining the therapeutic effect on psoriasis.
  • the psoriasis indicator gene is a gene described in i) or iii
  • an increase in the expression of the psoriasis indicator gene indicates that psoriasis is more likely to have progressed further. Is shown.
  • a decrease in the expression of the psoriasis indicator gene indicates that psoriasis is more likely to progress further.
  • the severity of psoriasis can be determined based on differences in expression levels. That is, when the psoriasis indicator gene is a gene described in i) or iii), the degree of increase in the expression of the psoriasis indicator gene correlates with the severity of psoriasis. Alternatively, when the psoriasis indicator gene is a gene described in ii) or iv), the degree of decrease in the expression of the psoriasis indicator gene correlates with the severity of psoriasis.
  • the present invention provides a transgenic non-human having an increased expression intensity in the skin of the AD indicator gene or a gene functionally equivalent to the AD indicator gene according to any of a), c) and c ′).
  • the present invention relates to an animal model of atopic dermatitis comprising an animal. According to the present invention, it has been clarified that the expression intensity of the AD indicator gene described in a) increases in the rash area of a patient with atopic dermatitis. Similarly, it was revealed that the expression intensity of the AD indicator gene described in c) and c) was increased in the rash-free area of patients with atopic dermatitis. Therefore, animals that artificially enhance the expression level of the AD indicator gene described in any of a), c ) and c ') or a gene functionally equivalent to the AD indicator gene in the skin are atopic With dermatitis model animals You can use it.
  • the present invention provides a transgenic non-drug which has reduced expression intensity in the skin of the AD indicator gene or a gene functionally equivalent to the AD indicator gene according to any of b), d) and d ').
  • the present invention relates to an animal model of atopic dermatitis comprising a human animal. According to the present invention, it has been clarified that the expression intensity of the AD indicator gene described in b) is reduced in the rash area of a patient with atopic dermatitis. Similarly, it became clear that the expression intensity of the AD indicator gene described in d) and d ′) was reduced in the eruption of atopic dermatitis patients.
  • animals in which the expression level of the AD indicator gene described in any of b), d) and d, or the gene functionally equivalent to the AD indicator gene in the skin is artificially reduced, It can be used as a model animal for atopic dermatitis.
  • the present invention also relates to a psoriasis model animal comprising a transgenic non-human animal having an increased expression level in the skin of the psoriasis indicator gene described in i) or iii) or a gene functionally equivalent to the psoriasis indicator gene.
  • the expression intensity of the psoriasis indicator gene described in i) increases in the rash of psoriatic patients.
  • the expression intensity of the psoriasis indicator gene described in iii) was increased in the rash-free area of psoriatic patients. Therefore, an animal in which the expression level of the psoriasis indicator gene described in i) or iii) or a gene functionally equivalent to the psoriasis indicator gene in the skin is artificially enhanced can be used as a psoriasis model animal.
  • the present invention also relates to a psoriasis model animal comprising a transgenic non-human animal having a reduced expression level in the skin of the psoriasis indicator gene described in ii) or iv) or a gene functionally equivalent to the psoriasis indicator gene.
  • the expression intensity of the psoriasis indicator gene described in ii) is reduced in the rash of psoriatic patients.
  • the expression intensity of the psoriasis indicator gene described in iv) was reduced in the rash-free area of psoriatic patients. Therefore, an animal in which the expression level of the psoriasis indicator gene described in ii) or iv) or a gene functionally equivalent to the psoriasis indicator gene in the skin is artificially reduced can be used as a model animal for psoriasis. .
  • a functionally equivalent gene is a gene that encodes a protein having the same activity as that clarified in the protein encoded by the indicator gene.
  • Representative examples of functionally equivalent genes include the counterpart of the indicator gene in the animal species that the test animal originally has.
  • the genes described in the groups A) to D> are functionally equivalent genes in mice.
  • A) Group-The genes described in Group D) are desirable indicator genes when screening according to the present invention is performed using mice.
  • the present invention has clarified the counterpart in mice of the AD indicator gene described in a) to d).
  • the mouse interaction percentages for the indicator genes described in a) to d) are described as A) to D), respectively.
  • an atopic dermatitis model animal can be created by adjusting the expression level of these counterparts or by administering them. That is, the present invention relates to a method for producing an atopic dermatitis model animal by regulating the expression levels of the genes described in A) to D). Alternatively, the present effort is directed to a method of producing an animal model of atopic dermatitis, which comprises a step of administering a protein encoded by the genes described in A) to D) or an antibody of the protein to a non-human animal. It relates to a manufacturing method.
  • the genes described in A) or C can induce atopic dermatitis by increasing their expression levels. it can.
  • an atopic dermatitis model animal can be created by administering a gene selected from these gene groups or a protein encoded by the gene. All of these counterparts are the remains of mice. Because it is a gene, it is desirable to administer genes and proteins to mice when administering them.
  • the gene group described in B) or D) induces atopic dermatitis by suppressing the expression level, like the gene group described in any of b), d) and d '). be able to.
  • atby dermatitis can be created by suppressing the expression of a gene selected from these genes and the activity of the protein encoded by the gene.
  • Antisense nucleic acid or RNAi can be used to suppress expression.
  • Administration of an activity inhibitor such as an antibody is effective for regulating the activity of a protein. That is, atopic dermatitis is induced by administering these components to an animal, ie, a mouse, having the gene group described in B) or D) innately.
  • the atopic dermatitis model animal is useful for elucidating in vivo changes in atopic dermatitis. Furthermore, using the atopic dermatitis model animal to elucidate the further function of the indicator gene and evaluating a drug targeting the gene are of great significance.
  • the atopic dermatitis model animal according to the present invention is useful for elucidating the mechanism of atopic dermatitis and for testing the safety of screened compounds.
  • a screening system for searching for a compound having an action to restore it can be constructed.
  • an increase in the expression level refers to a state in which the indicator gene is introduced as a foreign gene and is forcibly expressed, or a state in which the transcription and translation of the indicator gene originally provided in the test animal are enhanced. And any state in which the degradation of the protein as a translation product is suppressed.
  • a decrease in the expression level refers to a state in which the transcription of the indicator gene provided in the test animal and the translation into the protein are inhibited, or the expression of the protein as a translation product. Means any of the states where decomposition is promoted.
  • the gene expression level can be confirmed, for example, by a difference in signal intensity on a DNA chip as shown in Examples.
  • the activity of the protein as a translation product can be confirmed by comparison with a normal state.
  • transgenic animals include animals into which the indicator gene has been introduced and forced to be expressed, animals in which the indicator gene has been knocked out, and animals in which the gene has been replaced (knock-in) with other genes.
  • transgenic animals into which antisense DNA against the indicator gene, DNA encoding ribozyme, DNA functioning as a decoy nucleic acid, or the like has been introduced can also be used as the transgenic animal in the present invention.
  • an animal in which a mutation is introduced into the coding region of the indicator gene to enhance or suppress its activity 4 or is hardly degraded, or an animal modified to a degradable amino acid sequence can be shown. Mutations in the amino acid sequence can include substitutions, deletions, insertions, or additions.
  • the expression itself of the indicator gene of the present invention can also be regulated.
  • transgenic animals by targeting specific genes. That is, a method in which a gene and an egg are mixed and treated with calcium phosphate, or a method in which a gene is directly introduced into a nucleus of a pronuclear stage egg under a phase contrast microscope with a minute pipe (microinjection method, US Pat. No. 4,873,191). Transgenic animals can be obtained by methods using embryonic stem cells (ES cells). In addition, a method of inserting a gene into a retroviral vector and infecting an egg, a method of introducing a gene into an egg via sperm, and a sperm vector method have also been developed.
  • ES cells embryonic stem cells
  • the sperm vector method is a genetic recombination method in which a foreign gene is attached to sperm or incorporated into sperm cells by a method such as electroporation, and then fertilized by an egg to introduce the foreign gene.
  • a promoter whose transcription is regulated by a substance such as an appropriate drug is used as the promoter used in the expression vector
  • the expression level of the exogenous indicator gene in the transgenic animal can be adjusted by administering the substance.
  • the transgenic animal used as a model animal for atopic dermatitis or psoriasis of the present invention can be prepared using any vertebrate other than human. Specifically, transgenic animals in which various genes have been introduced or their expression levels have been altered in vertebrates such as mice, rats, porch egrets, miniature pigs, goats, sheep, and porch have been created. .
  • the present invention relates to a method for screening a candidate compound for treating atopic dermatitis.
  • the AD indicator gene is a gene selected from the group described in any of a :) to d), and c ′) and d ′).
  • the expression level of the gene selected from the group described in a) is significantly increased in the eruption area of the same patient as that of the non-eruption area of the atopic dermatitis patient.
  • the expression level of the gene selected from the group described in b) is significantly lower in the rash area of the same patient than in the rash area of the atopic dermatitis patient.
  • Genes selected from the groups described in c) and c ') have significantly increased expression levels in the eruptions of atopic dermatitis patients as compared to healthy subjects.
  • the expression levels of the genes selected from the groups described in d) and d ′) are significantly lower in the atopic part of atopic dermatitis patients than in healthy persons.
  • treatment of atopic dermatitis can be performed by selecting a compound capable of reducing the expression level of the AD indicator genes. You can get medicine.
  • the AD indicator gene of the group b), d) or d ' by selecting a compound capable of increasing the expression level of the AD indicator gene, a therapeutic agent for atopic dermatitis is selected. Can be obtained.
  • metalloproteinase secret
  • CTSZ cathepsin Z precursor
  • CCSZ cathepsin Z precursor
  • Proprotein convertase subtilisin / kexin typel tissue inhib itor of metalloproteinases N beta-migrating plasminogen activator in ibi tor I, IL-13Ral, IFN-beta 2a (IL-6), heparin-binding EGF-like growth factor , GM-CSFR beta, interleukin 8 (IL8), MCP-1, EBIl-ligand chemokine, SLC N GRO-beta, monocyte chemotactic protein-2, CCR1, lymph node homing receptor / L-selectin, endothelial leukocyte
  • Preferred genes for c,) group BTF3 protein homologue, general tran scription factor I IF, polypeptide 2, 30kDa, alternative activated macro phage specific CC chemokine 1, complement component 1, q subcomponent, beta polypeptides transforming growth factor, beta receptor III (betagl yean, 300kD), branched chain alpha-ketoacid dehydrogenase kinase ⁇ ATPas e, Ca ++ transporting, ubiquitous ⁇ tyrosinase-related protein 1 histidi ne ammonia- lyase, androgen-regulate d short-chain dehydrogenase / reductas e 1, gap junction protein, beta 3, 31kD (connexin 31), KI 0440, lympho id -restricted membrane protein (LRMP) S raatrilysin (MMP7), specific granule protein (28 kDa) (SGP28) type I
  • Preferred genes for d,) group genes Idl, BTG2, zinc finger protein 36, C3H type-like 1, EGRl (early growth response 1), MIP-1-alpha, MCP1, turao rnecrosis factor receptor superfamily, member 13B, HB15 / CD83, CD95, FAS, CD69, T cell receptor delta locus N caspase 3, apoptosis-related cys teine protease ⁇ serine (or cysteine) proteinase inhibitor, clade I (neu roserpin), member 1, SERPINE1, prostaglandin D2 synthase 21kDa (brain), cholesterol 25-hydroxylase, glutathione S-transferase M3 (brain), prote in phosphatase 5, catalytic subunit phosphodiesterase 3B, regulator of G-protein signaling 16, hepar in-binding EGF-like growth factor ⁇ pleio rophin, weel tyrosine kinase
  • AD indicator genes have not been altered in psoriatic patients. In other words, it can be said that the gene whose expression level has been specifically changed in atopic dermatitis patients. By using these AD indicator genes, it is possible to evaluate the therapeutic effect specific to atopic dermatitis symptoms.
  • the present invention relates to a method for screening a candidate compound for a therapeutic agent for psoriasis.
  • the psoriasis indicator gene is a gene selected from the group described in any of i) to iv).
  • the expression level of the gene selected from the group described in i) is significantly increased in the rash of the same patient as compared to the non-rash of the psoriasis patient.
  • the gene selected from the group described in ii) has a significantly lower expression level in the rash area of the same patient compared to the non-rash area of the psoriatic patient.
  • the gene selected from the group described in i) has a significantly increased expression level in the eruption area of psoriatic patients as compared to healthy persons. And the expression level of the gene selected from the group described in iv) is significantly lower in the eruption-free part of psoriatic patients than in healthy persons.
  • a therapeutic agent for psoriasis can be obtained by selecting a compound capable of reducing the expression level of the psoriasis indicator gene.
  • a therapeutic agent for psoriasis can be obtained by selecting a compound capable of increasing the expression level of the psoriatic index gene.
  • genes preferred as group genes cellular retinoic acid binding protein 2, proteasome (prosome, macropain) activator subunit 2, interferon in swiped 6-1 b protein ⁇ heat shock 70kDa protein 4, flap structure-specific endonuclease 1, NME1 , Eye 1 in-dependent kinase inhibitor 3, ubiquitin-conjugating enzyme E2C, calreticulin N CDC2 gene, liver arginase (AR Gl), connexin 43 (GJAl, Cx43), interleukin 1 receptor antagonist ⁇ ATP-binding cassette, sub-family A (ABCl), member 12, M-phase phosphoprotein
  • arylsulfatase F potassium inwardly-rectifying channel, subfamily J, member 15, BUB1 budding uninniDited by benz imidazoles 1 homolog beta (yeast), SPllO nuclear body protein isoform b , Guanylate binding protein 1 (GBP1), GM2 gangli oside activator protein N complement factor B preproprotein ⁇ squalene epoxidase ⁇ solute carrier family 5 (sodium / glucose cotransporter), member
  • Preferred genes for the group actin, alpha 2, smooth muscle, aorta, actin, gamma 2, smooth muscle, enteric N cisplatin resistance associated ⁇ growth arrest-specific 6, insulin- ⁇ ike growth factor binding protein 6 (IGFBP6), insulin induced protein 1 (INSIG1), PDGF receptor beta-like tumor suppressor (PRLTS), R-ras ⁇ sarcospan (Kras oncogene-associated gene), f ibroolast growth factor (FGF) receptor-1, fibronectin 1 isoform 1 preproprotein ⁇ chromosome 21 open reading frame 25, seven in absentia homolog 1 (Drosophila), fatty acid desaturase 1, fatty acid desaturase 2, Rho- related BTB domain containing 3, matrilin 2, adipose specific 2, LI 386
  • PF4 platelet factor 4
  • actin actin
  • gamma 2 smooth muscle
  • enteric v interferon alpha, beta and omega
  • DNA topoisomerase I DNA topoisomerase I
  • CYP3A4 cycl in-dependent kinase 2
  • vascular endothelial growth factor- D ABL1 N adducin 1 (alpha) isoform G
  • KLRC3, RAB2 l-acylglycerol-3-phospate 0-acyl transferase 2
  • tryptase a ⁇ pha, homolog of Yeast RRP4, MCM3, hemoglobin, delta, KIAA1089, zinc finger protein 44 (KOX 7), arylacetamide deacetylase (esterase), synuc synein, gam ma, elastase 2, neutrophil ⁇ CYP3A5, FCGR3A (CD16), likely ortholog of mouse neural in 1, pyruvate carboxylase ⁇ 2 ', 5
  • Preferred genes as group genes: H2B histone family, member G, cholin ergic receptor, nicotinic, beta polypeptide 4, related to the N terminus of tre, laminin, gamma 2 isoform b, interleukin 8, Kruppel- ⁇ ike facto r 4 (gut) N Al strom syndrome 1, and occ ⁇ udin
  • a compound that increases the expression level of a gene is a compound that has an action that promotes any of the steps of gene transcription, translation, and protein expression. Further, in the present invention, a compound that reduces the expression level of a gene is a compound that has an effect of inhibiting any of these steps.
  • the method for screening a candidate compound for treating an allergic disease (or psoriasis) of the present invention can be performed in vivo or in vitro. This screening can be performed, for example, according to the following steps.
  • the indicator gene is selected from the group described in any one of the above a) to c) and any one of c,) and d ′) (for psoriasis, any one of i) to iv) Genes functionally equivalent to any of the genes can be used.
  • a functionally equivalent gene is a gene that encodes a protein having an activity similar to the activity clarified in the protein encoded by the indicator gene.
  • a representative example of a functionally equivalent gene is a counterpart of the indicator gene in the animal species that the test animal originally has.
  • atopic Dermatitis model animals can be used as the test animal in the screening method of the present invention.
  • Atopic dermatitis model animals are known.
  • a natural dermatitis effort model using NC / Nga mouse has been reported.
  • a total of 8 doses of mite antigen (5 ig / ear) administered to the pinna of this mouse at 2-3 day intervals can induce symptoms very similar to human atopic dermatitis after 2 weeks.
  • the screening according to the present invention can be performed by administering a candidate compound to this system and tracking the change in the expression level of the indicator gene of the present invention.
  • the effect of the drug candidate compound on the expression level of the indicator gene is monitored. Can be evaluated. Fluctuations in the expression level of the indicator gene in the biological sample derived from the test animal can be monitored by the same method as the above-described test method of the present invention.
  • the indicator gene is a gene described in any of the groups a), c), and c ') (for psoriasis, the gene is group i) or iii))
  • Drug candidate compounds that reduce the expression level are identified by the genes listed in b), d) and d ') (for psoriasis, ii) or iv).
  • drug candidate compounds can be screened by selecting a drug candidate compound that increases the expression level.
  • the screening according to the present invention can be performed by collecting a skin tissue sample from a test animal and comparing the expression level of the indicator gene with a control to which a candidate compound cannot be brought into contact.
  • Methods for collecting and preparing skin tissue samples are known.
  • Such a screen allows selection of drugs that are involved in various ways in the expression of the indicator gene. Specifically, for example, drug candidate compounds having the following actions can be found.
  • the indicator gene is one of the groups a), c) and c ') (for psoriasis, iii)
  • the indicator genetic potato is a gene described in any of the groups b), d) and d ') (for psoriasis, the group ii) or iv):
  • a candidate compound is brought into contact with cells expressing the indicator gene, and the indicator gene is selected from the group consisting of group a), group c), and group c ') (i. ) Or iii)), a compound that reduces the expression level should be expressed in any of the b), d) and d ') groups (in the case of psoriasis, In the case of the gene described in group ii) or iv), a method for selecting a compound that increases the expression level can be mentioned. This screening can be performed, for example, according to the following steps.
  • the indicator gene of (1) a compound that reduces the expression level of the gene is used, and the indicator described in any one of groups b), d) and d ') (for psoriasis, group ii) or iv)
  • a step of selecting a compound that increases the expression level of the gene the cell that expresses the indicator gene inserts the indicator gene into an appropriate expression vector, and introduces the vector into an appropriate host cell Can be obtained by doing so.
  • host cells will produce the indicator gene of the present invention. Anything that can be expressed may be used. Examples of host cells in the host-vector system include Escherichia coli, yeast, insect cells, animal cells, and the like, and available vectors can be appropriately selected.
  • Examples of a method for introducing a vector into a host include a biological method, a physical method, and a chemical method.
  • Biological methods include, for example, a method using a virus vector, a method using a specific receptor, a cell fusion method (HVJ (sendivirus), polyethylene glycol (PEG), an electric cell fusion method, Nuclear fusion method (chromosome transfer)).
  • Examples of the physical method include a microinjection method, an electoral opening method, and a method using a gene part take / regane (gene gun).
  • Chemical methods include calcium phosphate precipitation, ribosome method, DEAE dextran method, protoplast method, erythrocyte ghost method, erythrocyte membrane ghost method, and microcapsule method.
  • skin cells such as Langerhans cells, mast cells, T cells, eosinophils, B cells, neutrophils, or basophils can be used as cells expressing the indicator gene.
  • Cells found in tissues can be used.
  • differentiation can be induced by stimulating human primary epidermal keratinocytes (keratinocytes), NHEK (Normal Human Epidermal Keratinocyte) with TGF-j3 or sodium butyrate (eg, Geng Wang EXPERIMENTAL CELL RESEARCH 198, 27-30 (1992)).
  • keratinocytes human primary epidermal keratinocytes
  • NHEK Normal Human Epidermal Keratinocyte
  • TGF-j3 or sodium butyrate eg, Geng Wang EXPERIMENTAL CELL RESEARCH 198, 27-30 (1992)
  • An intracellular structure called corn ied envelope (CE) is formed along with the fraction.
  • the formation of CE or the gene expression of CE constituent molecules can be used as an index to confirm the separation.
  • the cells thus differentiated are useful for screening in the present invention.
  • Skin cells T cells, eosinophils, mast cells, basophils, B cells, Langerhans cells, and neutrophils can also be used as cells found in skin tissue.
  • Stock Skin cells are suitable for the screening method of the present invention in that a large amount of homogeneous cells can be obtained and that culturing is easy.
  • the following are examples of skin cell lines that can be used in the present invention.
  • T cells Jurkat (ATCC TIB-152), Molt-4 (ATCC CRL-1582), H9 (ATCC HTB-176)
  • HMC-1 Single cell mast cell
  • One cell line B cell DND39, Raji (ATCC CCL-86)
  • HL-60 ATCC CCL-240
  • a candidate compound is brought into contact with the established skin cells. Thereafter, the expression level of the indicator gene in the established skin cells is measured, and compared with a control not contacted with the candidate compound, any one of the groups a), c), and c ′) (for psoriasis, For the indicator gene described in group i) or iii)), a compound that decreases the expression level of the gene, and any of group b), d) and d ') (ii) for psoriasis) For the indicator gene described in the group or iv), a compound that increases the expression level of the gene is selected.
  • the expression level of the indicator gene can be compared not only by the expression level of the protein encoded by the gene, but also by detecting the corresponding mRNA.
  • To compare expression levels by mRNA Performs the mRNA sample preparation step as described above instead of the protein sample preparation step. Detection of mRNA and protein can be carried out by a known method as described above.
  • a transcription regulatory region of the indicator gene of the present invention can be obtained, and a reporter assay system can be constructed.
  • the reporter-assay system refers to an atsey system that screens for a transcriptional regulator that acts on the transcriptional regulatory region, using the expression level of a reporter gene located downstream of the transcriptional regulatory region as an index.
  • the present invention provides a method for screening a therapeutic agent for atopic dermatitis or psoriasis, comprising the following steps, wherein the indicator gene is any one of a) to, and c ′) and d ′) (for psoriasis) Relates to a method which is any gene selected from the group described in any of i) to iv) or a gene functionally equivalent to the indicator gene.
  • the indicator gene described in any of the groups a), c) and c ') (for psoriasis, the group i) or iii))
  • a compound that reduces the expression level of the reporter gene, and an indicator gene described in any one of the groups b), d) and d ') (for psoriasis, the group ii) or iv) Selecting the compound that increases the expression level of the porter gene
  • transcription control region examples include a promoter, an enhancer, and a CMT box, a TATA box, and the like which are usually found in a promoter region.
  • reporter genes As reporter genes, CAT (chloramphenicol acetyl transferase) gene, luciferase (lucif erase) gene, growth hormone gene, etc. are used. Can be
  • the transcription regulatory region of each indicator gene in the present invention can be obtained as follows. That is, first, based on the nucleotide sequence of the cDNA disclosed in the present invention, screening is performed from a human genomic DNA library such as a BAC library or YAC library by PCR or a method using hybridization, and the cDNA is screened. Obtain a genomic DNA clone containing the sequence. Based on the obtained genomic DNA sequence, the transcription control region of the cDM disclosed in the present invention is estimated, and the transcription control region is obtained. The obtained transcription regulatory region is cloned so as to be located upstream of the reporter gene to construct a reporter construct. The resulting reporter construct is introduced into a cultured cell line to obtain a transformant for screening.
  • One of the groups a), c), and c ') (for psoriasis, group i) or i ii) is compared with a control in which the transformant is contacted with the candidate compound and not contacted with the candidate compound.
  • a compound that reduces the expression level of the reporter gene is used, and any one of the groups b), d) and d ') (for psoriasis, the group ii) or iv
  • the screening of the present invention can be performed by selecting a compound that increases the expression level of the reporter gene.
  • the present invention provides a method for screening a therapeutic agent for atopic dermatitis, which comprises the following steps, wherein the indicator gene is any one of a) to c) and any one of c ′) and d ′) (for psoriasis, i) group-iv) a method which is any gene selected from the group described in group) or a gene functionally equivalent to the indicator gene.
  • a compound having an activity of inhibiting the activity can be screened.
  • Compounds obtained in this manner suppress the action of each of the indicator genes described in any of the groups a), c) and c ') (for psoriasis, the groups i) and iii). Control.
  • atopic dermatitis or psoriasis
  • a compound having an activity to promote its activity is screened. can do.
  • the compound thus obtained promotes the function of the indicator gene described in any of the groups b), d) and d ') (for psoriasis, the group ii) or iv) .
  • atopic dermatitis or psoriasis
  • Test candidate substances used in these screenings include steroid derivatives and other compound specimens synthesized by existing chemical methods, compound specimens synthesized by combinatorial chemistry, extracts of animal and plant tissues, and microorganisms. Examples include a mixture containing a plurality of compounds such as a culture, and a sample purified from the mixture.
  • kits include substrate compounds used to detect the label, It is also possible to package the culture media and containers, positive and negative standard samples, and instructions and the like describing the use of the kit.
  • the compound selected by the screening method of the present invention is useful as a therapeutic agent for atopic dermatitis.
  • antisense DNA that can suppress the expression of any of the AD indicator genes according to any of a), c), and c, is also useful as a therapeutic agent for atopic dermatitis.
  • an antibody that recognizes a protein encoded by any of the AD indicator genes described in any of a :),, and) is also useful as a therapeutic agent for atopic dermatitis.
  • the AD indicator gene described in any of a), c), and c ′) is a gene whose expression is increased in the rash area of atopic dermatitis patients. Therefore, a therapeutic effect on atopic dermatitis can be expected by suppressing the expression of these genes or the functions of the proteins encoded by these genes.
  • any of the AD indicator genes described in any of b), d) and d '), and the protein itself encoded by the gene are also useful as a therapeutic agent for atopic dermatitis .
  • the compound selected by the screening method of the present invention is useful as a therapeutic agent for psoriasis.
  • an antisense DNA that can suppress the expression of any of the psoriasis indicator genes described in i) and iii) is also useful as a therapeutic agent for psoriasis.
  • an antibody that recognizes a protein encoded by any of the psoriasis indicator genes described in i) or iii) is also useful as a therapeutic agent for psoriasis.
  • the indicator gene described in i) or i ii) is a gene whose expression is increased in the rash of psoriasis patients. Therefore, a therapeutic effect on psoriasis can be expected by suppressing the expression of these genes or the functions of the proteins encoded by these genes.
  • any of the psoriasis indicator genes described in ii) or iv) and the proteins themselves encoded by the genes are also useful as therapeutic agents for psoriasis.
  • the therapeutic agent for allergic disease or psoriasis of the present invention contains a compound selected by the screening method as an active ingredient, and is produced by mixing with a physiologically acceptable carrier, excipient, diluent, or the like. can do.
  • the therapeutic agent for allergic disease or psoriasis of the present invention can be administered orally or parenterally for the purpose of ameliorating allergic symptoms or psoriasis.
  • dosage forms such as granules, powders, tablets, capsules, solvents, emulsions, and suspensions can be selected.
  • Examples of the injection include subcutaneous injection, intramuscular injection, and 0 ⁇ internal preparation.
  • a therapeutic effect can be achieved by introducing a gene encoding the protein into a living body using a gene therapy technique.
  • Techniques for treating a disease by introducing a gene encoding a protein that produces a therapeutic effect into an organism and expressing the gene are known.
  • antisense DNA can be incorporated downstream of an appropriate promoter sequence and administered as an antisense RNA expression vector.
  • this expression vector is introduced into mononuclear cells of an allergic disease patient, the antisense of these genes is expressed, and the therapeutic effect of allergy can be achieved by reducing the expression level of the genes.
  • Methods for introducing an expression vector into mononuclear cells are known in vivo and in vivo.
  • the dose varies depending on the age, sex, weight and condition of the patient, therapeutic effect, administration method, treatment time, or the type of active ingredient contained in the pharmaceutical composition. It can be administered in the range of 1 mg to 500 mg, preferably in the range of 0.5 mg to 20 mg. However, since the dosage varies depending on various conditions, a dosage lower than the above-mentioned dosage may be sufficient, and a dosage exceeding the above-mentioned range may be required in some cases.
  • the present invention provides artby's dermatitis immobilized with a probe for measuring at least one AD indicator gene selected from the groups a) to d), and any of the groups) and d ').
  • a DNA chip for diagnosis Alternatively, the present invention provides a DNA chip for diagnosing psoriasis, on which a probe for measuring at least one type of psoriasis indicator gene selected from any of groups i) to iv) is immobilized.
  • the type of indicator gene to be measured is arbitrary. The greater the number of indicator genes, the more judgments can be made based on more indicators. In general, measuring more indicators increases the accuracy of the diagnosis.
  • measuring a plurality of indicator genes it is advantageous to select genes having different properties. Genes that are considered to have different expression level mechanisms or different functions of the proteins encoded by the genes can be referred to as genes having mutually different properties.
  • atopic dermatitis and psoriasis can be measured by targeting the AD indicator gene described in a) -d) and c ') and d') and the psoriasis indicator gene described in i) -iv). Both can be detected by the same DNA chip.
  • the following example can be shown as an example of combining indicator genes.
  • the following combinations of indicator genes contribute to the improvement of the accuracy of allergic tests.
  • Proteases and protease inhibitors are indicators of a balance between tissue disruption and architecture. That is, among the indicator genes of the present invention, for a gene selected from the genes included in the protease group and the gene included in the protease inhibitor, a probe for detecting the gene is integrated, and a chip for detecting atopic dermatitis is obtained. It can be.
  • the indicator genes included in each group can be found from the list of indicator genes shown at the end of the description. For example, the imbalance between marauder P-3 (Matrix Metalloproteinase-3) and TIMP-1 (Tissue Inhibitor of MMP-1) It has been reported that the eruption may cause chronic rash. Therefore, the combination of protease and protease inhibitor is significant as a combination of indicator genes for allergic monogenic disease.
  • Each of these combinations is a combination of substances that are in a mutual relationship between a ligand and a receptor.
  • the immune response can also be viewed as the result of an interaction between these substances. Therefore, by combining these indicator genes, it may be possible to determine the state of skin tissue immunologically.
  • As the indicator gene both a ligand and a receptor-related molecule may be selected, or when only one of them is indicated as the indicator gene in the present invention, only one of them is used as the indicator gene. You can also choose.
  • extracellular matrix proteins examples include collagen and the like.
  • Cytoskeletal proteins include keratin, small prolin rich protein, involucrin, and others.
  • intercellular adhesion molecules include cadherin, desmocholine and the like.
  • the transcription factor can be jun, fos, or myc.
  • lipid mediators and lipid molecules that support Paria function Metabolism can be determined from the expression level of lipid metabolizing enzymes.
  • ⁇ includes pnospholipase A2, cyclooxygenase-2, prostaglandin D 2 synthase, or Fatty acid desaturase 1,2.
  • a probe capable of detecting the selected gene is selected for any combination of a plurality of genes selected from the genes constituting the groups a) and b).
  • the accumulated tips for atopic dermatitis testing are effective.
  • a gene of at least 10 or more, for example, 30 or more, preferably 50 or more, more preferably 60 or more, further preferably 80 or more, or 100 or more is selected from the group a). can do.
  • group b) usually 10 or more, for example, 30 or more, preferably 50 or more, more preferably 60 or more, and still more preferably 80 or more genes can be selected.
  • genes of usually 10 or more, for example, 30 or more, preferably 50 or more, more preferably 60 or more, more preferably 80 or more are selected from the group c) and the group Z or c ′). be able to.
  • a gene of usually 10 or more, for example, 30 or more, preferably 50 or more, more preferably 60 or more, and still more preferably 70 or more should be selected.
  • Atopic dermatitis testing chips comprising a combination of a gene selected from group a) and a gene selected from group c) and / or c ') are also effective for increasing the test accuracy. .
  • a tip for atopic dermatitis testing consisting of a combination of a gene selected from group b) and a gene selected from group d) and / or d '; may be used to increase the testing accuracy. It is effective for
  • a psoriasis test chip according to the present invention can be obtained.
  • the psoriasis indicator gene can be combined in the same manner as in the atopic dermatitis test chip described above. All prior art documents cited in the present specification are incorporated herein by reference. BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 is a graph showing the expression level of the IL-4 gene in skin tissues of patients with atopic dermatitis and healthy subjects.
  • the vertical axis shows the copy number of the IL-4 gene
  • the horizontal axis shows the skin tissue cases used in the analysis.
  • FIG. 2 is a graph showing the expression level of the IL-13 gene in skin tissues of patients with atopic dermatitis and healthy subjects.
  • the vertical axis shows the copy number of the IL-13 gene
  • the horizontal axis shows the skin tissue cases used for the analysis.
  • FIG. 3 is a graph showing the expression level of the IL- ⁇ gene in the skin tissue of a healthy patient with atopic dermatitis.
  • the vertical axis shows the copy number of the IL- ⁇ gene
  • the horizontal axis shows the skin tissue cases used for analysis.
  • Example 1 Analysis of the expression of Dila arenal in skin tissue of patients with atopic dermatitis using Affimetrics Genchip
  • Consent was obtained from 12 patients with atopic dermatitis and 4 from healthy subjects. And acute lesions, normal skin from healthy subjects, and three skin specimens (three thighs) from each site. The site of the acute lesion was determined based on the diagnostic criteria of the Japanese Society of Dermatology (Journal of the Japanese Dermatological Association 104: 1210 (1994)). Table 1 shows the clinical information of atopic dermatitis patients whose skin was collected.
  • the three skin biopsy (3 mm in diameter) collected were immersed in Isogen (Nippon Gene; Wako Pure Chemical Industries) and homogenized using an Ultratax T8 homogenizer (IKA). After homogenization, total RNA was extracted according to the manual of Isogen. A black-mouthed form was added, and the mixture was centrifuged with stirring to collect an aqueous layer. Next, isopropanol was added, and the mixture was centrifuged with stirring to collect the precipitate. The precipitate was rinsed with 75% ethanol and centrifuged, and the precipitate was collected as total RNA. The collected total RNA was further purified using the R Neasy Mini kit (QIAGEN) according to the manual.
  • Isogen Natural Gene
  • IKA Ultratax T8 homogenizer
  • the T7-(dT) 24 primer consists of a nucleotide sequence obtained by adding (dT) 24 to the nucleotide sequence of the T7 promoter as follows.
  • biotin-labeled cRNA was synthesized using the BioArray High Yield RNA Transcription Labeling Kit. CRNA was purified using an RNeasy Spin column (QIAGEN) and fragmented by heat treatment.
  • the positive and negative were determined by comparing the fluorescence intensity of the mismatch between the probe match and the probe match.
  • ⁇ T ⁇ ⁇ has a variation of 50 times or more, ⁇ ⁇ 10 10 to 50 times, ⁇ 3 to 10 times, ⁇ 2 to 3 times, one has no change,
  • ⁇ ⁇ ⁇ ⁇ indicates that the fluctuation is 50 times or more, ⁇ ⁇ 10 is 10 to 50 times, ⁇ 3 is 3 to 10 times, ⁇ is 2-3 times, ⁇ is no change, ⁇ indicates 1/50 or less, ⁇ ⁇ indicates 1/50 to 1/10, ⁇ I indicates 1/10 to 1/3, and indicates 1/3 to 1/2.
  • ⁇ ⁇ ⁇ ⁇ ⁇ has a fluctuation of 50 times or more, ⁇ ⁇ 10 10 to 50 times, ⁇ 3 to: L0 times, ⁇ 2 to 3 times, — indicates no change, ⁇ [ ⁇ [Is 1/50 or less, ⁇ 1 is 1/50 ⁇ : 1/10 times, ⁇ is 1/10 ⁇ : 1/3 times, ⁇ is 1/3 ⁇ : 1/2 times Is shown.
  • the gene encodes a humoral factor or a membrane protein, a neutralizing antibody, the humoral factor itself, or a soluble receptor can be administered to the experimental animal.
  • a humoral factor or a membrane protein a neutralizing antibody
  • the humoral factor itself a neutralizing antibody
  • a soluble receptor a soluble receptor
  • Mite antigen (Dermat ophagoides pteronyssinus 5 / zg / site) was intradermally administered to the auricle and back skin of SPF NC / Nga mice (6 weeks old) 9 times at 3 day intervals in total. Ear edema measurements and back skin symptoms were observed weekly. Blood was collected for total IgE concentration before mite antigen administration, 14 days after administration, and 28 days after administration, and measured with a mouse IgE measurement kit (Yamasa soy sauce). As a control, a non-sensitized group was taken, and the test was carried out using 20 animals (10 animals: dissected 14 days after the start of mite antigen administration, 10 animals: 28 S after the start of Dau antigen administration).
  • pathological examination showed that in the auricle skin of the sensitized group, epidermal thickening, inflammatory cell infiltration into dermis and subcutaneous tissue (neutrophils, eosinophils and lymphocytes), edema
  • proliferation of connective tissue, degranulation of mast cells, etc. were observed with slight to moderate changes, confirming that dermatitis was formed.
  • Ear skin and back skin were collected from unsensitized mice and sensitized mice (14 and 28 days after sensitization), immersed in Isogen (Nippon Gene; Wako Pure Chemical Industries), and homogenized with NS-310E; Homogenized under ice-cooling using Nichion Medical Science Instrument Co., Ltd.). After homogenization, total RNA was extracted according to the manual of Isogen. A black-mouthed form was added, and the mixture was centrifuged with stirring to collect an aqueous layer. Next, isopropanol was added, and the mixture was centrifuged with stirring to collect the precipitate. The precipitate was rinsed with 75% ethanol and centrifuged, and the precipitate was collected as total RNA. The collected total RNA was further purified using the RNeasy Mini kit (QIAGEN) according to the manual.
  • RNA extracted from the pinna of each individual of 10 animals per group was collected, and T7- (dT) 24 Aiiiersham Pharmacia Biotech) was used as a primer, and the total RNA extracted from Afiymetri cotyledons was used.
  • T7- (dT) 24 Aiiiersham Pharmacia Biotech) was used as a primer, and the total RNA extracted from Afiymetri cotyledons was used.
  • reverse pre-kappa copy was performed using Superscript II Reverse Transcriptase (Life Technologies) to prepare single-stranded cDNA.
  • the T7- (dT) 24 primer consists of a nucleotide sequence obtained by adding (dT) 24 to the nucleotide sequence of the T7 promoter as follows.
  • DNA Ligase, DNA polymerase I and RNase H were added to synthesize a double-stranded cDNA. After extracting the cDNA with phenol-form, it was subjected to Phase Lock Gels and purified by ethanol precipitation.
  • biotin-labeled cRNA was synthesized using the BioArray High “iield RNA Transcription Labeling Kit.
  • the cRNA was purified using RNeasy Spin colunm (QIAGEN) and fragmented by heat treatment.
  • the lOti g cRNA was added to the Hybridization Cocktail according to the Expression Analysis Technical Manual. This was placed in a DNA chip and hybridized at 45 ° C for 16 hours. GeneChip (R > Murine Genome U74Av2, Bv2, Cv2 (Affymetrix)) was used as a DNA chip.
  • Streptavidin-Phycoerythrin was added for staining. After washing, a mixture of normal goat IgG and biotinylated goat anti-streptavidin IgG antibody was added to the array. Furthermore, for the purpose of enhancing the fluorescence intensity, Streptavidin-Phycoerythrin was added again for staining. After washing, it was set on a scanner and analyzed with DNA chip analysis software.
  • the expression fluorescence intensity was measured using Suite, a DNA chip analysis software, and the data was analyzed. First, Absolute analysis was performed on all chips according to the GeneChip Analysis Suite User Guide, and the gene expression level of each sample used was measured.
  • Average DifFerence (Avg Difif), which is the average value of the difference in fluorescence intensity between the perfect match and the mismatched probe cell, was also calculated.
  • ⁇ ⁇ ⁇ ⁇ ⁇ fluctuates more than 50 times, ⁇ ⁇ 10 ⁇ 50 times, Byeon Byeon is 3 ⁇ 10 times, 2 is 2-3 times, ⁇ is no change, ⁇ ⁇ ⁇ ⁇ is 1/50 or less, / ⁇ ⁇ is 1/50 ⁇ : 1/10 times, ⁇ 1 indicates 1/10 to: 1/3 times, and ⁇ indicates 1/3 to: 1/2 times.
  • HCK HCK
  • HPTP HPTP epsilon I mRNA for protein
  • ⁇ ⁇ ⁇ T ⁇ fluctuates 50 times or more, ⁇ ⁇ 10 10 to 50 times, ⁇ 3 3 to 10 times, ⁇ 2 to 3 times, one does not change, ⁇ ⁇ ⁇ indicates 1/50 or less, ⁇ ⁇ 1 indicates 1/50 to 1/10 times, ⁇ indicates 1/10 to: 1/3 times, and ⁇ indicates 1/3 to 1/2 times.
  • Transcription factor and related molecule Transcriptional regulator protein
  • genes were identified as genes that can be used as indicators of atopic dermatitis. Any of these genes can be used as an indicator gene in the present invention.
  • HME metalloproteinase
  • cathepsin Z precursor CTSZ
  • CTSZ cathepsin Z precursor
  • pro-cathepsin L major excreted protein MEP
  • squamous cell carcinoma antigen serine protease inhibitor / 1343— s—at / S6689 6 / ⁇ -006919 / NP—008850 / Biochem. Biophys. Res. Commun. 181 (1), 51-58 (199 1)
  • SCCA2 squamous cell carcinoma antigen 2
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  • S100 family proteins small (10-14kDa) calcium binding protein
  • S100A7 psoriasin (S100A7) /34458_at/AA586894/NM_002963/NP_002954/J.Invest.Derma tol. 97 (4), 701-712 (1991)
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  • TNFAIP6 tumor necrosis factor, alpha-induced protein 6
  • COMP cartilage oligomeric matrix protein
  • Immunoglobulin, Immunoglobulin receptor, and related molecule immunoglobulin lambda light chain (constant region) / 33273_f_at / X57809 /-/ ⁇ / SEQ ID NO: 3 (base sequence) SEQ ID NO: 4 (amino acid sequence)
  • IgG low affinity Fc fragment receptor CD32 / 37688_f_at / M31932 / NM_021642
  • SEQ ID NO: 5 base sequence
  • SEQ ID NO: 6 amino acid sequence
  • HCK hemopoietic cell protein-tyrosine kinase
  • ornithine decarboxylase ODC (EC 4.1.1.17) / 36203_at / X16277 / NM_002539 / NP_0 02530 / DNA 6 (3), 179-187 (1987)
  • N 1T nicotinamide N-methyltransferase
  • SEQ ID NO: 10 amino acid sequence
  • PNP purine nucleoside phosphorylase
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  • interferon-inducible protein p78 (MX1) / 37014_at / M33882 / NM_002462 / NP_00245
  • IGFBP4 insulin-like growth factor binding protein 4
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  • LAPTm5 ⁇ ysosomal-associated mult i transmembrane protein
  • TSSC3 tumor suppressing subtransferable candidate 3
  • PA-FABP fatty acid binding protein homologue
  • heparin binding protein HBpl7
  • FGF-BPl heparin binding protein
  • fibrinogen like 2 / 39591— s— at / Z36531 / _006682 / NP_006673 / Gene 160 (2), 25 262 (1995) preferentially expressed in memory T lymphocytes and at low levels or not at all in naive T lymphocytes.
  • SERPINB7 serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 7) / 35577_at / AF027866 / NM_003784 / NP_003775 / J. Biol. Chem. 272 (24), 15373-15380 (1997)
  • KIM0353 I desmuslin (intermediate filament protein) / 39544_at / AB002351 / AF 359284 / AAK57487 / Proc.Natl.Acad.Sci. Biophys Res Con 1995 Dec 5; 217 (1): 238—44
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  • 1103 at / M11567 / ⁇ — 001145 / NP— 001136 / Bioch emistry 24 (20), 5494-5499 (1985)
  • PCK1 phosphoenolpyruvate carboxykinase
  • tyrosinase no 38927— i_at / M27160 / N—000372 / NP— 000363 / Proc. Natl. Acad.
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  • aldehyde dehydrogenase 3 family member A2 / 40409_at / U46689 / NM_000382 / P_0 00373 / Nat. Genet. 12 (1), 52-57 (1996)
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  • H0XA9 class I homeoprotein
  • 37809 at / U41813 / O—002142 / NP—002133 / SEQ ID NO: 13 (base sequence)
  • SEQ ID NO: 14 amino acid sequence
  • PZF promyelocytic leukemia zinc finger protein
  • FKHL7 forkhead / winged helix-like transcription factor 7 (FKHL7) / 41027_at / AF07
  • Beta-mi croseminoprotein isoform a PSP94
  • Beta-mi croseminoprotein isoform b PSP57
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  • ITM2A integrated membrane protein 2A
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  • SEQ ID NO: 18 amino acid sequence
  • DKFZP434G0310 hyperthetical protein
  • 33332 at / Z93241 /-/-/ SEQ ID NO: 19
  • PCP4 Purkinje cell protein 4
  • TRIM2 (tripartite motif-containing 2) / 39382_at / AB011089 / M_015271 / NP_0560 86 / EMBO J. 20 (9), 2140-2151 (2001)
  • MTIV metallothionein IV
  • ADAM9 (a disintegrin and metalloproteinase domain 9) / 34761_r_at / U41766 / N
  • SCCA2 squamous cell carcinoma antigen 2
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  • germline oligomer ic matrix protein (COMP) / 40161_at / L32137 / N _000095 / NP_0
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  • hemoglobin alpha l / 31525_s_at / J00153 / NM_000558 / NP_000549 / Proc. Natl. Aca d. Sci. U.S.A. 71 (6), 2300-2304 (1974)
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  • HBB beta-globin
  • ATP-binding cassette, sub-family G (WHITE), member 1 / 41362—at / X91249 / M-0 04915 / P—004906 / Am.J.Hum.Genet. 59 (1), 66-75 (1996)
  • MVP major vault protein
  • SEQ ID NO: 3 base sequence
  • SEQ ID NO: 4 amino acid sequence
  • small proline- rich protein IB (cornif in) / 37160_at / 19888 / NM_003125 / NP_003
  • myosin heavy chain 12 (MY05A) / 40571_at / U90942 / M_000259 / NP_000250 / Genomi cs 19 (3), 407-416 (1994)
  • lung type- I cell membrane-associated protein (Tla-2) / 41870_at / AF030428 / N _006474 / NP_006465 / Am. J. Respir. Cell Mol. Biol. 19 (1), 143-149 (1998) metallothionein IV (MTIV ) / 521_at / U07807 / M_032935 / NP_116324 / Biochemistry
  • RBP4 retinol binding protein 4, plasma
  • ATF3 activating transcription factor 3 / 287—at / L19871 / Marauder—001674 / NP-001 665 / J. Biol. Chem. 269 (22), 15819-15826 (1994) 1 7 2; - eleven 1
  • MITF microphthalraia-associated transcription factor
  • EGR2 (early growth response 2) / 37863— at / J04076 / N— 000399 / NP— 000390 / Proc. Natl. Acad. Sci. U.S.A. 85 (19), 7164-7168 (1988)
  • TR3 nuclear receptor subfamily 4, group A, member 1 / 279_at / L13740 / NM_0
  • cytochrome P450 4F2 (CYP4F2) / 1350_at / U02388 / NM_001082 / NP_001073 / FEBS Let t. 348 (1), 70-74 (1994)
  • HSDll 11-beta-hydroxys teroi d dehydrogenase
  • ODC ornithine decarboxylase
  • SEQ ID NO: 41 amino acid sequence
  • WAFl I eye 1 in-dependent kinase inhibitor 1A (p21, Cipl) / 2031_s_at / U03106 / NM-1-000389 / NP—000380 / Cell 75 (4), 817—825 (1993)
  • GEM GTP binding protein overexpressed in skeletal muscle
  • G0S8 I RGS2 (regulator of G-protein signaling 2) / 37701_at / L13463 / NM_0029 23 / NP— 002914 / DNA Cell Biol. 13 (2), 125-147 (1994)

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Abstract

A gene showing a difference in expression level between a rash site and a no-rash site in a patient with atopic dermatitis or a patient with psoriasis is found out. Also, a gene showing a difference in expression level between a no-rash site in such a disease and a normal subject is found out. It is clarified that these genes are useful as indicators in examining atopic dermatitis or psoriasis or screening a remedy therefor. That is to say, a method of examining atopic dermatitis or psoriasis and a method of screening a compound for treating these diseases based on the comparison of expression levels of these indicator genes.

Description

明細書 ァトピー性皮膚炎の検查方法 技術分野  Description Method for detecting atopic dermatitis
本発明は、 アトピー性皮膚炎の検査方法に関する。 背景技術  The present invention relates to a method for testing atopic dermatitis. Background art
アトピー性皮膚炎等のアレルギー性疾患は、 多因子性の病気 (multifactorial diseases)と考えられている。 これらの病気は多くの異なる遺伝子の発現の相 互作用によって起こり、 これらの個々の遺伝子の発現は、 複数の環境要因によ つて影響を受ける。 このため、 特定の病気を起こす特定の遺伝子を解明するこ とは、 非常に困難である。  Allergic diseases such as atopic dermatitis are considered to be multifactorial diseases. These diseases are caused by the interaction of the expression of many different genes, and the expression of these individual genes is affected by several environmental factors. For this reason, it is very difficult to elucidate the specific gene that causes a specific disease.
またアレルギー性疾患には、 変異や欠陥を有する遺伝子の発現や、 特定の遺 伝子の過剰発現や発現量の減少が関わっていると考えられている。 病気に関し て遺伝子発現が果たしている役割を解明するためには、 遺伝子が発症にどのよ うに関わり、 薬剤などの外的な刺激が遺伝子発現をどのように変化させるのか を理解する必要がある。  In addition, allergic diseases are thought to be related to the expression of genes having mutations or defects, or to overexpression or reduced expression of specific genes. To understand the role of gene expression in disease, it is necessary to understand how genes are involved in the pathogenesis and how external stimuli such as drugs alter gene expression.
さて、 現在アレルギー' 14疾患の診断においては、 一般に、 問診、 家族歴、 そ して本人の既往症の確認が量要な要素となっている。 またアレルギーをより客 観的な情報に基づいて診断するために、 血液を試料とする試験方法や、 アレル ゲンに対する患者の免疫学的な応答を観察する方法も実施されている。 前者の 例として、 アレルゲン特異的 IgE測定、 白血球ヒスタミン遊離試験、 あるいは リンパ球幼若化試験等が挙げられる。 アレルゲン特異的 IgE の存在は、 そのァ レルゲンに対するアレルギー反応の証明である。 しかし患者によっては、 必ず しもアレルゲン特異的な IgE を検出できるとは限らない場合もある。 また、 そ の測定原理上、 診断に必要なアレルゲンの全てに対して、 試験を実施しなけれ ばならない。 白血球ヒスタミン遊離試験やリンパ球幼若化試験は、 免疫システ ムのアレルゲンに対する反応を in vitroで観察する方法である。 これらの方法 は、 操作が煩雑である。 Now, in general, in the diagnosis of allergic diseases, interviews, family histories, and confirmation of the patient's history are important factors. In order to diagnose allergies based on more objective information, test methods using blood samples and methods of observing patients' immunological responses to allergens are also being implemented. Examples of the former include allergen-specific IgE measurement, leukocyte histamine release test, and lymphocyte blastogenesis test. The presence of allergen-specific IgE is evidence of an allergic reaction to the allergen. However, in some patients, it may not always be possible to detect allergen-specific IgE. Also, Due to the measurement principle, tests must be performed for all allergens required for diagnosis. The leukocyte histamine release test and lymphocyte blastogenesis test are methods for observing the response of the immune system to allergens in vitro. These methods are complicated in operation.
一方、 患者を実際にアレルゲンに接触させたときに観察される免疫応答をァ レルギ一の診断に役立てる方法 （後者） も公知である。 プリック ·テスト、 ス クラッチ 'テスト、 パッチ'テスト、 皮内反応、 あるいは誘発試験等が、 この 種の試験に含まれる。 これらの試験では、 患者のアレルギー反応を直接診断す ることができる反面、 実際に被検者をアレルゲンに曝露する侵襲を伴う検査で あると言うことができる。  On the other hand, a method is also known in which the immune response observed when a patient is actually contacted with an allergen is used to diagnose allergens (the latter). Such tests include prick tests, scratch 'tests, patch' tests, intradermal reactions, or provocation tests. While these tests can directly diagnose a patient's allergic reaction, they can be described as tests involving invasive exposure of the subject to allergens.
この他、 アレルゲンに関わらず、 アレルギー反応の関与を証明するための試 験方法も試みられている。 たとえば、 血清 IgE値が高値である場合、 その患者 にはアレルギー反応が起きていると推定することができる。 血清 IgE値は、 ァ レルゲン特異 IgEの総量に相当する情報である。 アレルゲンの種類に関わらず I gE の総量を決定することは容易であるが、 非ァトピー型気管支炎喘息等の疾患 を持つ患者では、 IgEが低値となる場合がある。  In addition, test methods have been attempted to prove the involvement of allergic reactions regardless of the allergen. For example, a high serum IgE level may indicate that the patient has an allergic reaction. The serum IgE value is information corresponding to the total amount of allergen-specific IgE. Although it is easy to determine the total amount of IgE regardless of the type of allergen, IgE may be low in patients with diseases such as non-atopic bronchitis asthma.
従って、 アレルゲンに関わらず、 アレルギー患者の病態の把握や治療方針の 決定に役立てることができる診断指標が求められていた。 さらに、 患者に対す る侵襲が小さく、 しかも診断に必要な情報を容易に得ることができるアレルギ 一性疾患のマーカーが提供されれば有用である。 このようなマーカーは、 ァレ ルギー性疾患の発症に深く関与していると考えられるので、 診断のみならず、 ァレルギ一症状のコント口ールにおいても、 重要な標的となる可能性がある。 発明の開示  Therefore, there has been a demand for a diagnostic index that can be used to understand the condition of an allergic patient and to determine a treatment policy, regardless of the allergen. Furthermore, it would be useful if markers for allergic diseases could be provided that would have minimal invasiveness to the patient and could easily provide the information needed for diagnosis. Since such markers are thought to be deeply involved in the development of allergic diseases, they may be important targets not only in diagnosis but also in controlling allergic symptoms. Disclosure of the invention
本発明はこのような状況に鑑みて為されたものであり、 その目的は、 アトピ 一性皮膚炎の検査を可能とする新しい指標を提供することにある。 さらに本発 明は、 該指標に基づくァトピー性皮膚炎の検査方法、 およぴァトピー性皮膚炎 治療薬候補化合物のスクリ一ユング方法を提供することを目的とする。 The present invention has been made in view of such a situation, and an object of the present invention is to provide a new index capable of testing for atopic dermatitis. Further departure Akira aims to provide a method for examining atopic dermatitis based on the index and a method for screening a candidate compound for a therapeutic agent for atopic dermatitis.
本発明者らは上記課題を解決するために鋭意研究を行った。 すなわち、 アト ピ一性皮膚炎患者の皮疹部と同一の患者における無疹部、 およびアトピー性皮 膚炎患者の無疹部と健常者の皮膚との間で発現レベルに差が見られる遺伝子を 明ら力 こし、 アトピー性皮膚炎反応との関連性を明らかにすることにより、 ァ トピー性皮膚炎治療の新たな標的を見出すことができると考えた。  The present inventors have intensively studied to solve the above problems. That is, genes whose expression levels are different between the eruption in the same patient as the eruption of atopic dermatitis and the eruption in the atopic dermatitis patient and the skin of healthy subjects are identified. We clarified that we could find a new target for treatment of atopic dermatitis by clarifying its relationship with the atopic dermatitis response.
このような考えに基づき、 本発明者らは、 アトピー性皮膚炎患者の皮疹部と 同一の患者における無疹部、 およびアトピー性皮膚炎患者の無疹部と健常者の 皮膚との間で発現状態の違う遺伝子を探索した。 遺伝子の発現状態を比較する 生体試料としては、 被検者の皮膚組織を選択した。 実際に炎症が起きている皮 膚組織検体には病態形成に重要なリンパ球などが多く浸潤しており、 皮膚局所 における遺伝子発現解析を行えばァトピー性皮膚炎の病態の解明につながると 考えられる。  Based on this idea, the present inventors developed a rash in the same patient as the eruption of atopic dermatitis and between the rash in the patient with atopic dermatitis and the skin of healthy subjects We searched for genes with different states. The skin tissue of the subject was selected as a biological sample for comparing gene expression states. Skin tissue specimens that are actually inflamed are infiltrated with many lymphocytes, etc., which are important for the pathogenesis.Analysis of gene expression in the local skin is likely to elucidate the pathology of atopic dermatitis .
本発明者らは、 アトピー性皮膚炎患者の皮疹部と同一の患者における無疹部、 並びに健常者の皮膚で発現している遺伝子について、 ジーンチップを用いて発 現プロファイルを比較した。 2倍以上の発現変動のあった遺伝子を選別し、 遺 伝子の発現レベルを測定した。 そして、 以下の a)〜 、 並びに c' )および d' )の いずれかに記載の群から選択された指標遺伝子の発現が変動していることを確 認した。 更に本宪明者らは、— これらの指標遺伝子のマウスカウンターパ一トに ついて、 マウス皮膚炎モデルにおける発現レベルを解析し、 マウスの皮膚炎に 関連する指標遺伝子として A)〜D)のいずれかの群に記載の指標遺伝子を選択し た。  The present inventors compared the expression profile of a rash in the same atopic dermatitis patient as the rash in the same patient and genes expressed in the skin of healthy subjects using a gene chip. Genes with a two-fold or more expression fluctuation were selected, and the gene expression levels were measured. Then, it was confirmed that the expression of an indicator gene selected from the group described in any of the following a) to c) and c ′) and d ′) fluctuated. Furthermore, the present inventors analyzed the expression levels of these indicator genes in a mouse dermatitis model for mouse counterparts, and identified any of A) to D) as indicator genes related to mouse dermatitis. The indicator genes described in the group were selected.
a)〜 、 並びに c' )および d' )、 そして A)〜D)のいずれかに記載した各指標遺 伝子の塩基配列は既知である。 a)〜 の各指標遺伝子によってコードされる蛋 白質の機能は、 後に記載するデータ 1〜データ 4の Reference の項に示した論 文に記載されている。 加えて、 c' )および d' )の各指標遺伝子によってコードさ れる蛋白質の機能は、 後に記載するデータ 7およびデータ 8の Reference の項 に示した論文に記載されている。 また A)および B)の各指標遺伝子によってコー ドされる蛋白質の機能は、 データ 5およびデータ 6の、 そして C)および D)の各 指標遺伝子によってコードされる蛋白質の機能は、 データ 1 3およびデータ 1 4の Reference の項に示した論文にそれぞれ記載されている。 あるいは本発明 による乾癬の検査方法における乾癬指標遺伝子 i)〜： Lv)の塩基配列、 および該指 標遺伝子によってコードされるアミノ酸配列は公知である。 本発明の各指標遺 伝子の公知の塩基配列の GenBankァクセシヨン番号は、 下記データ 9〜データ 1 2 (ヒト） に記載したとおりである。 更に i)〜： Lv)の各指標遺伝子によってコ ードされる蛋白質の機能は、 後に記載するデータ 9〜データ 1 2の Reference の項に示した論文に記載されている。 これらの遺伝子群の中にはァトピー性皮 膚炎との直接的な関連性について報告されている遺伝子もあるが、 多くの遺伝 子についてはアレルギー性疾患との関連を示す報告はない。 また、 アトピー性 皮膚炎との関連性が報告されている遺伝子についても、 同じタイミングで共発 現変動する他の遺伝子との組み合わせという観点では報告はない。 同様に乾癬 の指標遺伝子についても、 その検査や治療剤のスクリーユングの指標として有 用であることは報告されていない。 The nucleotide sequences of the indicator genes described in any of a) to, c ') and d'), and A) to D) are known. The functions of the proteins encoded by each of the indicator genes a) to) are described in the Reference section of Data 1 to Data 4 described later. It is stated in the sentence. In addition, the functions of the proteins encoded by the c ′) and d ′) indicator genes are described in the papers described later in Data 7 and Data 8 in the Reference section. The functions of the proteins encoded by the indicator genes of A) and B) are shown in Data 5 and Data 6, and the functions of the proteins encoded by the indicator genes of C) and D) are shown in Data 13 and These are listed in the papers listed in the Reference section of Data 14 respectively. Alternatively, the base sequences of psoriatic indicator genes i) to Lv) in the psoriasis test method according to the present invention and the amino acid sequence encoded by the indicator genes are known. The GenBank accession numbers of the known nucleotide sequences of the indicator genes of the present invention are as described in the following data 9 to data 12 (human). Further, the functions of the proteins encoded by each of the indicator genes i) to Lv) are described in the papers described in the Reference section of Data 9 to Data 12 described later. Although some of these genes have been reported to have a direct association with atopic dermatitis, many genes have not been reported to be associated with allergic disease. In addition, there is no report of a gene reported to be associated with atopic dermatitis from the viewpoint of combination with other genes that co-express and fluctuate at the same time. Similarly, it has not been reported that the indicator gene for psoriasis is useful as a marker for testing or screening for therapeutic agents.
ァトピー性皮膚炎患者の皮疹部と同一の患者における無疹部、 およびァトピ 一性皮膚炎患者の無疹部と健常者との間において、 指標遺伝子の発現レベルに 変動が観察されたという事実は、 本発明の指標遺伝子とアトピー性皮膚炎症状 との深い結びつきを表している。 また、 ダニアレルゲン感作マウスの耳介皮膚 とダニァレルゲン非感作マウスの耳介皮膚において、 上記指標遺伝子のマウス におけるカウンターパートの発現レベルに差が見られることも、 本発明の指標 遺伝子とアトピー性皮膚炎症状との結びつきを裏付けている。  The fact that a change was observed in the expression level of the indicator gene between the rash in the same patient as the atopic dermatitis patient and the rash in the same patient, and between the rash in the patient with atopic dermatitis and healthy subjects This indicates a deep association between the indicator gene of the present invention and atopic dermatitis condition. Furthermore, the difference in the expression level of the counterpart of the above indicator gene in mice between the auricle skin of mite allergen-sensitized mice and the auricle skin of mite allergen non-sensitized mice was also observed. It supports the connection with skin irritations.
更に本発明者らは、 このようにして選択された各遺伝子について、 乾癬患者 における発現レベルとの比較を試みた。 その結果、 アトピー性皮膚炎患者およ ぴ乾癬患者において、 特異的に発現レベルが変化している遺伝子群、 ならびに 両方の患者で共通して発現レベルが変化している遺伝子群とを明らかにした。 各疾患に固有の変化が見られる遺伝子群には、 各疾患に特異的な診断指標や治 療方法の標的遺伝子としての有用性が期待できる。 一方、 両方の疾患において 共通して発現レベルが変化する遺伝子群は、 皮膚炎症性疾患に共通の診断指標 や治療方法の標的遺伝子としての有用性が期待できる。 Further, the present inventors have determined that each gene selected in this way We tried to compare with the expression level in. As a result, we identified a group of genes whose expression levels were specifically changed in patients with atopic dermatitis and psoriasis, and a group of genes whose expression levels were commonly changed in both patients. . Genes that show changes specific to each disease can be expected to be useful as diagnostic indicators specific to each disease and target genes for treatment methods. On the other hand, a group of genes whose expression levels change in both diseases in common can be expected to be useful as diagnostic indices common to skin inflammatory diseases and target genes for therapeutic methods.
以上の知見に基づいて、 本発明者らは、 各指標遺伝子の発現レベル、 あるい は各指標遺伝子によってコードされる蛋白質の活性を指標とすることにより、 アトピー性皮膚炎あるいは乾癬の診断、 およぴ該疾患のための治療薬のスクリ —ユングが可能であることを見出し、 本発明を完成させた。  Based on the above findings, the present inventors have proposed the diagnosis and diagnosis of atopic dermatitis or psoriasis by using the expression level of each indicator gene or the activity of the protein encoded by each indicator gene as an indicator. The present inventors have found that it is possible to screen a therapeutic agent for the disease and complete the present invention.
すなわち本発明は、 以下のアトピー性皮膚炎の検査方法、 並びにアトピー性 皮膚炎治療薬候補化合物のスクリ一ユング方法に関する。  That is, the present invention relates to the following methods for examining atopic dermatitis and a method for screening a candidate compound for a therapeutic agent for atopic dermatitis.
〔1〕 次の工程 ( 1 ) 〜 （3 ) を含む、 アトピー性皮膚炎の検査方法であって、 指標遺伝子が次の a)〜d)、 並びに c' )および d' )のいずれかに記載の群から選択 されたいずれかの遺伝子である方法。  [1] A method for testing atopic dermatitis, comprising the following steps (1) to (3), wherein the indicator gene is any one of the following a) to d), and any of c ') and d') A method which is any gene selected from the group described.
( 1 ) 被検者の皮疹部および/または無疹部から採取された生体試料における 指標遺伝子の発現レベルを測定する工程  (1) A step of measuring the expression level of an indicator gene in a biological sample collected from a skin eruption and / or a rash of a subject
( 2 ) 工程 ( 1 ) で測定された発現レベルを、 指標遺伝子が a)または b)に記 载された遺伝子である場合には、 対照として同じ被検者の無疹部から採取 された生体試料における指標遺伝子の発現レベルと、 また指標遺伝子が c)、 c ) , d)、 および d' )のいずれかに記載された遺伝子である場合には、 対照 として健常者の生体試料における指標遺伝子の発現レベルと比較する工程、 および  (2) When the expression level measured in step (1) is the indicator gene described in a) or b), the expression level of the biological sample collected from the rash-free part of the same subject as a control The expression level of the indicator gene in the sample and, if the indicator gene is a gene described in any of c), c), d), and d '), the indicator gene in a biological sample of a healthy subject as a control Comparing with the expression level of
( 3 ) 工程 ( 2 ) の比較の結果、 指標遺伝子が a)、 c)および c，）に記載された 遺伝子の場合には対照と比較して発現レベルが高い場合に、 また指標遺伝 W (3) As a result of the comparison in step (2), when the indicator gene is the gene described in a), c) and c,), the expression level is higher than the control, W
6に To 6
子が b)、 d)および d' )に記載された遺伝子の場合には対照と比較して発現 レベルが低い場合に、 前記被検者はァトピー性皮膚炎を有すると判定する 工程  Determining that the subject has atopic dermatitis when the offspring of the genes described in b), d) and d ′) have a lower expression level compared to the control.
a)以下の遺伝子からなる、 皮瘙部における発現レベルがアトピー性皮膚炎患 者の無瘙部に比べて高い指標遺伝子群： cathepsin C、 metalloproteinase (HM E)、 airway trypsin-丄: Lke protease^ type IV collagenase^ cathepsin Z prec ursor (CTSZ)、 disintegrin- protease、 serine protease-like protein^ pro- c athepsin L (major excreted protein MEP)、 protease M、 skin collagenaseN trypsinogen IV b-formN SPUVE (protease, serine, 23)、 Proprotein convert ase subtilisin/kexin typel、 neutrophil gelatinase associated lipocalin^ squamous cell carcinoma antigen=serine protease inhibitor squamous eel 1 carcinoma antigen 2 (SCCA2) s tissue inhibitor of metalloproteinases^ mononcyte/neutrophil elastase inhibitor^ alpha 1— antitrypsin、 beta-mi gr ating plasminogen activator inhibitor I、 elafin、 interleukin-7 receptor s IL-13R al、 IFN- beta 2a (interleukin 6〉、 interleukin 4 receptor platele ΐ一 derived endothelial cell growth factor Λ pre— B cell enhancing factor (PBEF)、 heparin- binding EGF-丄 ike growth f actor s GM-CSFR beta、 interleuk in 8 (IL8)、 alternative activated macrophage specific CC chemokine 1、 M CP - 1、 EBIl-ligand chemokine^ SLCN lactotransferrin^ GRO— beta、 monocyte chemotactic protein- 2、 CCR1、 melanoma growth stimulatory activity (MGS A) I Gro alphas psoriasin (S100A7)、 MRP— 8 (S100A8〉、 MRP— 14 (S100A9)、 CaN 19 (S100A2)、 p cadherin lymph node homing receptor I L-selectinN endoth elial leukocyte adhesion molecule 1 (ELAM - 1〉、 130- kD pemphigus vulgaris antigen I Desmoglein 3、 leukocyte adhesion protein (LFA— 1/Mac - l/pl50, 9 5 family) beta、 desmocollins type 2b、 TNFAIP6 (tumor necrosis factor, a lpha-induced protein 6)、 CD24 signal transducer 130 antigen extracell ular variant / CD163、 0A3 antigenic surface determinant / CD47、 CD53 gl ycoproteinN T200 leukocyte common antigen (CD45) isoforml、 T200 leukocy te common antigen (CD45) isoform2、 T200 leukocyte common antigen (CD45) isoform3、 THY-l (CD90)、 monocyte/macrophage Ig - related receptor MIR- 7 I CD85、 leucocyte immunoglobulin- like receptor- 3 (LIR- 3)、 tenascin - C、 a lpha-1 type XV collagen、 cartilage oligomer ic matrix protein (C0MP)、 pr oteoglycan 1、 immunoglobulin lambda light chain、 Fc - epsilon - receptor ga 腿 a— chain、 IgG low affinity Fc fragment receptor (CD32)、 i腿 imoglobulin heavy constant gamma 3 (G3m marker)、 immunoglobulin kappa constant^ ly n、 hemopoietic cell protein- tyrosine kinase (HCK)、 protein tyrosine pho sphatase, receptor type, E isoforml、 protein tyrosine phosphatase, rece ptor type, E isoform2、 KIAA0687 / MAP4K4、 tartrate resistant acid phosp hatase type 5、 cholesterol 25- hydroxylase、 Phospholipid scraniblase 1、 m anganese superoxide dismutase (EC 1. 15, 1. 1)、 ornithine decarboxylase OD C (EC 4. 1, 1. 17)、 phospholipase A2， group IIA (platelets, synovial flui d)、 nicotinamide N- methyl transferase (NNMT)、 uridine phosphorylaseN aid ose reductase— like peptide^ 2'， 5' oligoadenylate synthetase isoform E16、 2'， 5' oligoadenylate synthetase isoform E18、 25， 5' oligoadenylate synth etase 2 isoform p69、 2' , 5' oligoadenylate synthetase 2 isoform p71、 L-k ynurenine hydrolase^ purine nucleoside phosphorylase (PNP ; EC 2. 4. 2. 1)、 25 , 5' oligoadenylate synthetase—丄 ike (59 kDa isoform)、 cytokeratin 丄 keratin 6A、 keratin 16、 actin related protein 2/3 complex, subunit IB (41 kD)、 myosin VA (heavy polypeptide 12, my ox in) ^ Small proline- rich p rotein SPRK、 small proline— rich protein 2A、 small proline— rich protein IB (cornif in) involucrin^ myosin IB、 interferon-inducible protein p78 (MX1)、 gamma - interferon— inducible protein (IP— 30)、 interferon— induced 1 7 - kDa/15 - kDa protein^ p27， interferon— alpha - inducible protein 27、 RAB31、 regulator of G - protein signalling 1 (BL34) N regulator of G - protein sign ailing 20、 STATU TNRC3、 insulin-like growth factor binding protein 4 (IGFBP4)、 cyclin B、 proto- oncogene (Wnt-5a)、 beta defensin 2 (聽 2)、 ne 1- related protein 2、 neuronal tissue- enriched acidic protein (NAP - 22)、 DKFZp58600118 I KIAA1199、 lysosoma丄一 associated multi transmembrane prote in (LAPTm5)、 KIAA0101、 KIAA0296、 serum amyloid Al、 tumor suppressing su btransferable candidate 3 (TSSC3)、 TYRO protein tyrosine kinase binding protein fatty acid binding protein homologue (PA- FABP)、 heparin bindi ng protein (HBpl7) I FGF - BP1、 transcobalamin I、 fibrinogen - like 2、 およ ぴ six transmembrane epithelial antigen of the prostate (STEAP) a) Indicator genes consisting of the following genes, whose expression level in the skin area is higher than that in the atopic area of atopic dermatitis patients: cathepsin C, metalloproteinase (HM E), airway trypsin-II: Lke protease ^ type IV collagenase ^ cathepsin Z prec ursor (CTSZ), disintegrin-protease, serine protease-like protein ^ pro- c athepsin L (major excreted protein MEP), protease M, skin collagenase N trypsinogen IV b-form N SPUVE (protease, serine, 23), Proprotein convertase subtilisin / kexin typel, neutrophil gelatinase associated lipocalin ^ squamous cell carcinoma antigen = serine protease inhibitor squamous eel 1 carcinoma antigen 2 (SCCA2) s tissue inhibitor of metalloproteinases ^ mononcyte / neutrophil elastase inhibitor ^ alpha 1- antitrypsin, beta-migrating plasminogen activator inhibitor I, elafin, interleukin-7 receptor s IL-13R al, IFN-beta 2a (interleukin 6>, interleukin 4 receptor platele ΐ 一 derived endothelial cell growth factor Λ pre- B cell enhancing factor (PBEF) , heparin- binding EGF-丄ike growth f actor s GM-CSFR beta, interleuk in 8 (IL8), alternative activated macrophage specific CC chemokine 1, M CP - 1, EBIl-ligand chemokine ^ SLC N lactotransferrin ^ GRO- beta, monocyte chemotactic protein-2, CCR1, melanoma growth stimulatory activity (MGS A) I Gro alpha s psoriasin (S100A7), MRP-8 (S100A8>, MRP-14 (S100A9), CaN 19 (S100A2), p cadherin lymph node homing receptor I L-selectin N endoth elial leukocyte adhesion molecule 1 (ELAM-1), 130-kD pemphigus vulgaris antigen I Desmoglein 3, leukocyte adhesion protein (LFA-1 / Mac-l / pl50 , 9 5 family) beta, desmocollins type 2b, TNFAIP6 (tumor necrosis factor, a lpha-induced protein 6), CD24 signal transducer 130 antigen extracell ular variant / CD163, 0A3 antigenic surface determinant / CD47, CD53 glycoprotein N T200 leukocyte common antigen (CD45) isoforml, T200 leukocyte common antigen (CD45) isoform2, T200 leukocyte common antigen (CD45) isoform3, THY-l (CD90) , Monocyte / macrophage Ig-related receptor MIR-7 I CD85, leucocyte immunoglobulin-like receptor-3 (LIR-3), tenascin -C, a lpha-1 type XV collagen, cartilage oligomeric matrix protein (C0MP), pr oteoglycan 1, immunoglobulin lambda light chain, Fc-epsilon-receptor ga thigh a-chain, IgG low affinity Fc fragment receptor (CD32), i thigh imoglobulin heavy constant gamma 3 (G3m marker), immunoglobulin kappa constant ^ ly n, hemopoietic cell protein -tyrosine kinase (HCK), protein tyrosine pho sphatase, receptor type, E isoforml, protein tyrosine phosphatase, receptor type, E isoform2, KIAA0687 / MAP4K4, tartrate resistant acid phosp hatase type 5, cholesterol 25-hydroxylase, Phospholipid scraniblase 1 manganese superoxide dismutase (EC 1.15, 1.1), ornithine decarboxylase ODC (EC 4.1, 1.17), phospholipase A2, group IIA (platelets, synovial flui d), nicotinamide N-methyl transferase (NNMT) ), Uridine phosphorylase N aid ose reductase-- like peptide ^ 2 ', 5' oligoadenylate synthetase isoform E16, 2 ', 5' oligoadenylate synthetase isoform E18, 25 , 5 'oligoadenylate synth etase 2 isoform p69, 2', 5 'oligoadenylate synthetase 2 isoform p71, Lk ynurenine hydrolase ^ purine nucleoside phosphorylase (PNP; EC 2. 4. 2. 1), 2 5, 5 'oligoadenylate synthetase-丄ike (59 kDa isoform), cytokeratin丄keratin 6A, keratin 16, actin related protein 2/3 complex, subunit IB (41 kD), myosin VA (heavy polypeptide 12, my ox in) ^ Small proline- rich protein SPRK, small proline— rich protein 2A, small proline— rich protein IB (cornif in ) involucrin ^ myosin IB, interferon-inducible protein p78 (MX1), gamma-interferon— inducible protein (IP— 30), interferon— induced 1 7-kDa / 15-kDa protein ^ p27, interferon-- alpha-inducible protein 27, RAB31, regulator of G-protein signaling 1 (BL34) N regulator of G-protein sign ailing 20, STATU TNRC3, insulin-like growth factor binding protein 4 (IGFBP4), cyclin B, proto-oncogene (Wnt-5a), beta defensin 2 (listening 2), ne 1-related protein 2, neuronal tissue-enriched acidic protein (NAP-22), DKFZp58600118 I KIAA1199, lysosoma丄 一 associated multi transmembrane prote in (LAPTm5), KIAA0101, KIAA0296, serum amyloid Al, tumor suppressing su btransferable candidate 3 (TSSC3), TYRO protein tyrosine kinase binding protein fatty acid binding protein homologue (PA-FABP), heparin bindi ng protein (HBpl7) I FGF-BP1, transcobalamin I, fibrinogen-like 2, and trans six transmembrane epithelial antigen of the prostate (STEAP)
b)以下の遺伝子からなる、 皮癡部における発現レベルがアトピー皮膚炎患者 の無痿部に比べて低い指標遺伝子群： kallikrein 1、 cathepsin V、 cystatin E /M、 SERPINB7 ^serine 、or cysteineノ proteinase innioitor, clade B (ovalb umin) , member 7)、 tissue inhibitor of metalloproteinase 4、 KIAA1775 (M T - protocadherin)、 keratin 18、 cytokeratin 15、 keratin 19、 smooth muscle myosin heavy chain 11, isoform SM2、 sciellin (SCEL〉、 KIAA0353/ desmusli n (intermediate filament protein)、 calponin 1、 desmin、 extracellular ma trix protein 2、 protein— tyrosine— phosphatase Dl、 KI 0537、 angiogenin b) An indicator group consisting of the following genes, whose expression level in the epidermis is lower than that in the atopic dermatitis patients: kallikrein 1, cathepsin V, cystatin E / M, SERPINB7 ^ serine, or cysteine proteinase innioitor, clade B (ovalb umin), member 7), tissue inhibitor of metalloproteinase 4, KIAA1775 (MT-protocadherin), keratin 18, cytokeratin 15, keratin 19, smooth muscle myosin heavy chain 11, isoform SM2, sciellin (SCEL), KIAA0353 / desmuslin (intermediate filament protein), calponin 1, desmin, extracellular matrix protein 2, protein— tyrosine— phosphatase Dl, KI 0537, angiogenin
(RNase A family, 5)、 RNase 4、 deoxyribonuclease I- like 2 (DNAS1L2) % ph osphoenolpyruvate carboxykinase (PCKl)、 carbonic anhydrase isozyme VI (CA6)、 3— hydroxy— 3— methy丄 glutary丄 coenzyme A synthase^ arylacetamide de acetylase、 ATPase, Cu++ transporting, alpha polypeptide (ATP 7 A) tyrosi nase (TYR)、 amylase, alpha 2B; pancreatic^ CMP-N-acetylneuraminic acid hydroxylase^ Aminomethy丄 transferase (glycine cleavage system protein T)ヽ monoamine oxidase A、 Aldehyde dehydrogenase 5 family, member Al、 CYTOCH ROME P450， SUBFAMILY IIIA, POLYPEPTIDE 5、 alcohol dehydrogenase 1A (cla ss 1)， alpha polypeptide^ alcohol dehydrogenase IB (class I) , beta poly peptide^ alcohol dehydrogenase 1C (class 1)， gamma polypeptide^ degener ative spermatocyte homolog (sphingol ipid delta 4 desaturase) FABP7 (fa tty acid binding protein 7)、 alpha- 2- glycoprotein 1， zinc、 peri丄 ipin、 F ABP4 (Fatty acid binding protein 4)、 lipoprotein lipase^ aldehyde dehyd rogenase 3 family, member A2、 phytanoyl - CoA hydroxylase interacting pro tein (KIAA0273)、 apolipoprotein D、 apolipoprotein E、 Hemoglobin alpha 1 chain (HBA1)、 Hemoglobin alpha 2 chain (HBA2)、 hemoglobin, gamma A (HB Gl)、 hemoglobin, gamma G (HBG2)、 hemoglobin, beta、 mammag丄 obin 1、 mamma globin 2、 secretoglobin, family ID, member 2、 delta sleep inducing pept ide, immunoreactor^ class I homeoprotein (H0XA9)、 beta- catenin- interact ing protein ICAT、 promyelocytic leukemia zinc finger protein (PLZF)、 GA TA3、 forkhead/winged helix - like transcription factor 7 (FKHL7)、 Inhibit or of DNA binding 4 (ID4)、 calcium channel, voltage- dependent, alpha 1H subunit、 sodium channel, nonvo 11 age-gat ed 1， beta、 Beta-microseminopro tein i soform a (PSP94〉、 Beta-microseminoprotein isoform b (PSPo 7八 test icular inhibin beta— B- subunit、 LIGl (ortholog of mouse integral membran e glycoprotein LIG- 1)、 WFSl (Wolfram syndrome 1)、 TM4SF3 (transmembrane(RNase A family, 5), RNase 4, deoxyribonuclease I-like 2 (DNAS1L2) % ph osphoenolpyruvate carboxykinase (PCKl), carbonic anhydrase isozyme VI (CA6), 3-hydroxy-3-methy 丄 glutary 丄 coenzyme A synthase ^ arylacetamide de acetylase, ATPase, Cu ++ transporting, alpha polypeptide (ATP 7 A) tyrosinase (TYR), amylase, alpha 2B; pancreatic ^ CMP-N-acetylneuraminic acid hydroxylase ^ Aminomethy 丄 transferase (glycine cleavage system protein T) ヽ monoamine oxidase A , Aldehyde dehydrogenase 5 family, member Al, CYTOCH ROME P450, SUBFAMILY IIIA, POLYPEPTIDE 5, alcohol dehydrogenase 1A (clas 1), alpha polypeptide ^ alcohol dehydrogenase IB (class I), beta poly peptide ^ alcohol dehydrogenase 1C (class 1), gamma polypeptide ^ degenerative spermatocyte homolog (sphingol ipid delta 4 desaturase) FABP7 (fatty acid binding protein 7), alpha-2-glycoprotein 1, zinc, peri 丄 ipin, FABP4 (Fatty acid binding protein 4), lipoprotein lipase ^ aldehyde dehyd rogenase 3 family, member A2, phytanoyl-CoA hydroxylase interacting protein (KIAA0273), apolipoprotein D, apolipoprotein E, Hemoglobin alpha 1 chain (HBA1), Hemoglobin alpha 2 chain (HBA2), hemoglobin, gamma A (HB Gl), hemoglobin, gamma G (HBG2), hemoglobin, beta, mammag 丄 obin 1, mamma globin 2, secretoglobin, family ID, member 2, delta sleep inducing peptide, immunoreactor ^ class I homeoprotein (H0XA9), beta-catenin- interacting protein ICAT, promyelocytic leukemia zinc finger protein (PLZF), GA TA3 forkhead / winged helix-like transcription factor 7 (FKHL7), Inhibit or of DNA binding 4 (ID4), calcium channel, voltage-dependent, alpha 1H subunit, sodium channel, nonvo 11 age-gat ed 1, beta, Beta-microseminopro tein i soform a (PSP94), Beta-microseminoprotein isoform b (PSPo 78 test specific inhibitor beta- B-subunit, LIGl (ortholog of mouse integral membran e glycoprotein LIG-1), WFSl (Wolfram syndrome 1), TM4SF3 (transmembrane
4 superfamily member 3)、 ΊΤΜ2Α (integral membrane protein 2A)、 claudin4 superfamily member 3), ΊΤΜ2Α (integral membrane protein 2A), claudin
8ヽ syndecan 4 (amphiglycan, ryudocan) ^ progesterone receptor membrane component 2、 peanut -l ike 1 (Drosophila)ヽ type 1 angiotensin II receptor, variant 1-5、 EphB6、 proteolipid proteinic betacellul in^ apMl (adipose most abundant gene transcript 1)、 proline rich 4 (lacrimal)、 prolactin- inducible protein^ HZF9、 skin-specific protein (xp32) N Crystall in, alph a B、 retinol binding protein 4、 Hepatocellular carcinoma antigen gene 5
Figure imgf000011_0001
8 ヽ syndecan 4 (amphiglycan, ryudocan) ^ progesterone receptor membrane component 2, peanut -like 1 (Drosophila) ヽ type 1 angiotensin II receptor, variant 1-5, EphB6, proteolipid proteinic betacellul in ^ apMl (adipose most abundant gene transcript 1), proline rich 4 (lacrimal), prolactin-inducible protein ^ HZF9, skin-specific protein (xp32) N Crystall in, alph a B, retinol binding protein 4, Hepatocellular carcinoma antigen gene 5
Figure imgf000011_0001
20、 DKFZP434G0310 (hypothetical protein)、 Purkinje cell protein 4 (PCP 4)、 141H5 cyclin Dl、 丄 oricrin、 TRIM2 (tripartite motif-containing 2)、 metallothionein IV ( TIV) N DKFZp586H2123、 transmembrane 4 superfamily m ember 11 (plasmolipin)、 DKFZp434A202、 KIAA0471, KIAA0450, KIAA0624, KIA A0633, partial cds、 KIAA0456, partial cds、 DKFZp564D206、 DKFZp586F1223、 Clorf21、 および DKFZp761F2014 20, DKFZP434G0310 (hypothetical protein), Purkinje cell protein 4 (PCP 4), 141H5 cyclin Dl, 丄 oricrin, TRIM2 (tripartite motif-containing 2), metallothionein IV (TIV) N DKFZp586H2123, transmembrane 4 superfamily m ember 11 (oliposome) , DKFZp434A202, KIAA0471, KIAA0450, KIAA0624, KIA A0633, partial cds, KIAA0456, partial cds, DKFZp564D206, DKFZp586F1223, Clorf21, and DKFZp761F2014
c) 以下の遺伝子からなる、 アトピー性皮膚炎患者の無疹部における発現レべ ルが健常者の発現レベルに比べて高い指標遺伝子群： P13- kinase associated p 85、 pho sphoeno Ipyruvat e carboxykinase (PCK1 nucleotide pyrophosphates e、 L-3-phosphoserine phosphatase^ L - 3 - phosphoserine- phosphatase homolog ue、 KIAA0369/ doublecortin and CaM kinase - like 1、 tartrate— resistant aci d phosphatase type 5、 pM5 protein^ ADAM9 (a disintegrin and metalloprot einase domain 9 Ubiquitin - conjugating enzyme E2E 1、 DKFZp586H2123、 SP UVE (protease, serine, 23)、 squamous cell carcinoma antigen 2 (SCCA2 connexin 43 (GJA1, Cx43 plakophilinN desmocollin type 4、 integrin alp ha - 2 subunit、 H-cadherin neural cell adhesion molecule (CALL) s cartila ge intermediate layer protein (CI LP) N lumican chondroitin sulphate pro teoglycan vers i can, VI splice-variant^ germline oligomeric matrix prote in (COMP)ゝ aspartylg丄 ucosaminidase lysyl hydroxylase isoform 2 (PL0D2) phospholipase A2, group IlA platelets, synovial fluid) GDP-L - fucose p yrophosp orylase (GFPP)、 glycogen debranching enzyme isoform 1 (AGL) alternatively spliced isoformヽ Gu protein/DDX21 : DEAD/H (Asp - Glu - Ala-As p/His) box polypeptide 21 lipoprotein lipase^ SMA5 hemoglobin, alpha 1、 hemoglobin, alpha 2 sickle cell beta - globin beta- globin (HBB) A-g a a globin G - gamma globin、 phospholipid transfer protein^ ATP— binding cassette, sub-family G (WHITE) , member 1 type 2 inositol 1, 4, 5-trisph l i ; ！ c) A group of indicator genes consisting of the following genes whose expression level in the eruption area of atopic dermatitis patients is higher than that in healthy subjects: P13-kinase associated p85, pho sphoeno Ipyruvat e carboxykinase (PCK1 nucleotide pyrophosphates e, L-3-phosphoserine phosphatase ^ L-3-phosphoserine- phosphatase homolog ue, KIAA0369 / doublecortin and CaM kinase-like 1, tartrate— resistant aci d phosphatase type 5, pM5 protein ^ ADAM9 (a disintegrin and metalloprot einase domain 9 Ubiquitin-conjugating enzyme E2E 1, DKFZp586H2123, SP UVE (protease, serine, 23), squamous cell carcinoma antigen 2 (SCCA2 connexin 43 (GJA1, Cx43 plakophilin N desmocollin type 4, integrin alp ha-2 subunit, H-cadherin) neural cell adhesion molecule (CALL) s cartilage intermediate layer protein (CI LP) N lumican chondroitin sulphate pro teoglycan vers i can, VI splice-variant ^ germline oligomeric matrix prote in (COMP) ゝ aspartylg 丄 ucosaminidase lysyl hydroxylase isoform 2 (PL0D2) phospholipase A2, group IlA platelets, synovial fluid) GDP-L-fucose p yrophosp orylase (GFPP), glycogen debranching enzyme isoform 1 (AGL) alternatively spliced isoform ヽ Gu protein / DDX21: DEAD / H (Asp -Glu-Ala-As p / His) box polypeptide 21 lipoprotein lipase ^ SMA5 hemoglobin, alpha 1, hemoglobin, alpha 2 sickle cell beta-globin beta-globin (HBB) Ag aa globin G-gamma globin, phospholipid transfer protein ^ ATP — Binding cassette, sub-family G (WHITE), member 1 type 2 inositol 1, 4, 5-trisph li;!
osphate receptorゝ MVP (major vault protein) C0G5 (component of oligome ric golgi complex 5)、 SIOO calcium- oinding protein A7 (psoriasin 1)、 Ca N19、 immunoglobulin lambda light chain^ immunoglobulin heavy constant g amma 3、 immunoglobulin kappa constant^ major histocompatibility complex, class II， DQ beta 1、 CIQB (complement component 1， q subcomponent, bet a polypeptide) s Guanine Nucleotide - Binding Protein Ral, Ras - Oncogene Re lated、 KIAA0440, RAB5、 KIAA0400/de ve 1 opment- and differentiation- enhanc ing factor 2、 alternative activated macrophage specific CC chemokine 1、 CC - chemokine MCP - 4、 small proline - rich protein IB (cornif in) ^ myosin he avy chain 12 (MY05A)、 M0P3、 RB18A、 TTF- I interacting peptide 12/腿 polosphate receptor ゝ MVP (major vault protein) C0G5 (component of oligome ric golgi complex 5), SIOO calcium- oinding protein A7 (psoriasin 1), Ca N19, immunoglobulin lambda light chain ^ immunoglobulin heavy constant g amma 3, immunoglobulin kappa constant ^ major histocompatibility complex, class II, DQ beta 1, CIQB (complement component 1, q subcomponent, bet a polypeptide) s Guanine Nucleotide-Binding Protein Ral, Ras-Oncogene Related, KIAA0440, RAB5, KIAA0400 / de ve 1 opment- and differentiation-enhancing factor 2, alternative activated macrophage specific CC chemokine 1, CC-chemokine MCP-4, small proline-rich protein IB (cornif in) ^ myosin he avy chain 12 (MY05A), M0P3, RB18A, TTF-I interacting peptide 12 / thigh pol
I and transcript release factor Mad4 homolog (Mad4)、 pituitary tumor- transforming protein 1、 SMAD5、 G0S2、 eye 1 in B、 Retinoblastoma 1、 M130 a ntigen extracellular variant (CD163)、 Z39IG、 perilipin、 apMl (adipose m ost abundant gene transcript 1)、 DKFZp586J0323、 KIAA1001S KIAA0766、 KIA A0101、 DJ971N18. 2/KIAA1162, lung type - 1 cell membrane-associated protei n (Tla— 2)、 metal lothi one in IV (MTIV)、 UTY (ubiquitously transcribed tet ratricopeptide repeat gene, Y chromosome) Apg - 1、 HUNKI/MCAPS I and transcript release factor Mad4 homolog (Mad4), pituitary tumor-transforming protein 1, SMAD5, G0S2, eye 1 in B, Retinoblastoma 1, M130 antigenic extracellular variant (CD163), Z39IG, perilipin, apMl (adipose m ost abundant gene) transcript 1), DKFZp586J0323, KIAA1001 S KIAA0766, KIA A0101, DJ971N18.2 / KIAA1162, lung type-1 cell membrane-associated protein (Tla-- 2), metal lothi one in IV (MTIV), UTY (ubiquitously transcribed tet ratricopeptide) repeat gene, Y chromosome) Apg-1, HUNKI / MCAP S
FHL2 (four and a half LIM domains 2)、 RBP4 (retinol binding protein 4, plasma) N およぴ ALG— 2/programmed cell death 6 FHL2 (four and a half LIM domains 2), RBP4 (retinol binding protein 4, plasma) N and ALG— 2 / programmed cell death 6
c' ) 以下の遺伝子からなる、 ァトビー性皮膚炎患者の無疹部における発現レ ベルが健常者の発現レベルに比べて高い指標遺伝子群： transforming growth f actor, beta receptor III (betaglycan, 300kD)、 BTF3 protein homologue、 h emoglobin, alpha 1、 hemoglobin, beta、 alternative activated macrophage specific CC chemokine 1、 Prolactin— Induced Protein、 branched chain alph a-ketoacid dehydrogenase kinase^ type I sigma receptor isoform 1、 type I sigma receptor isoform 2、 type I sigma receptor isoform 3、 type I sig ma receptor isoform 4、 type I sigma receptor isoform 5、 ΚΓΑΑ0664 protei n、 FK506 - binding protein IB isoform a、 FK506 - binding protein IB isoform b、 lymphoid -; restricted membrane protein (LRMP)、 specific granule prote in (28 kDa) (SGP28)、 ATPase, Ca++ transporting, ubiquitous^ general tra nscription factor I IF, polypeptide 2, 30kDa、 carboxypeptidase M、 tyrosi nase- related protein 1、 HCR (a- helix coiled- coil rod homologue) N FLJ125 25、 A - gamma globin、 complement component 1， q subcomponent, beta polype ptide、 SET binding factor 1 (SBF1)、 histidine ammoni a—lyase、 KIAA0440、 ESTs, Moderately similar to 2004399A chromosomal protein^ gap junction protein, beta 3， 31kD (connexin 31)、 androgen- regulated short-chain deh ydrogenase/reductase 1、 nuclear receptor subfamily 1， group H, member 2、 matrilysin (MMP7)、 および mnt- related transcription factor 1 c ') An indicator gene group consisting of the following genes, the expression level of which is higher in the eruptions of patients with atby dermatitis than that of healthy subjects: transforming growth factor, beta receptor III (betaglycan, 300kD), BTF3 protein homologue, hemoglobin, alpha 1, hemoglobin, beta, alternative activated macrophage specific CC chemokine 1, Prolactin—Induced Protein, branched chain alph a-ketoacid dehydrogenase kinase ^ type I sigma receptor isoform 1, type I sigma receptor isoform 2, type I sigma receptor isoform 3, type I sig ma receptor isoform 4, type I sigma receptor isoform 5, ΚΓΑΑ0664 protein, FK506-binding protein IB isoform a, FK506-binding protein IB isoform b, lymphoid-; restricted membrane protein (LRMP), specific granule prote in (28 kDa) (SGP28), ATPase, Ca ++ transporting, ubiquitous ^ general transcription factor I IF, polypeptide 2, 30kDa, carboxypeptidase M, tyrosinase-related protein 1, HCR (a- helix coiled- coil rod homologue) N FLJ125 25, A- gamma globin, complement component 1, q subcomponent, beta polypeptide, SET binding factor 1 (SBF1), histidine ammoni a-lyase, KIAA0440, ESTs, Moderately similar to 2004399A chromosomal protein ^ gap junction protein, beta 3, 31kD (connexin 31 ), Androgen- regulated short-chain dehydrodrogenase / reductase 1, nuclear receptor subfamily 1, group H, member 2, matrilysin (MMP7), and mnt-related transcription factor 1
d) 以下の遺伝子からなる、 アトピー性皮膚炎患者の無痧部における発現レべ ルが健常者の発現レベルに比べて低い指標遺伝子群： junD、 c-jun proto oncog ene、 c-fos、 GOS / Fos— B、 c- myc oncogene^ jun— B、 ATF3 (activating trans cr iption factor 3)、 AREB6、 ETR101ゝ ZFP36 (zinc finger protein 36)、 ets— 2、 EZF、 MITF (microphthalmia- associated transcription factor)、 EGRl (early growth response 1)、 EGR2 (early growth response 2)、 BTG2、 励- 3、 Idl、 Id2、 Id3、 TR3 (nuclear receptor subfamily 4， group A， member 1)、 NOT (n uclear receptor subfamily 4， group A, member 2)、 CL 100/dual specif icit y phosphatase 1、 cyclooxygenase-2 (hCox- 2)、 cytochrome P450 4F2 (CYP4F 2)、 prostaglandin D2 synthase^ Fatty acid desaturase 1、 Fatty acid desa turase 2、 cholesterol 25 - hydroxy上 ase、 11-beta-hydroxysteroid dehydrogen ase (HSD11)、 glutamate pyruvate transaminase (GPT)ヽ glycine decarboxyla se、 ornithine decarboxylase (ODC)、 GADD34/Protein phosphatasel regulato ry subunit 15A、 carboxypeptidase Z、 DKFZp434J214N Cdk - inhibitor p57KIP2、 1 3 ：—:： d) An indicator gene group consisting of the following genes, whose expression level in the atopic region of atopic dermatitis patients is lower than that of healthy subjects: junD, c-jun protooncogene, c-fos, GOS / Fos— B, c-mycocogene ^ jun— B, ATF3 (activating trans cription factor 3), AREB6, ETR101 ゝ ZFP36 (zinc finger protein 36), ets—2, EZF, MITF (microphthalmia- associated transcription factor) , EGRl (early growth response 1), EGR2 (early growth response 2), BTG2, excitation-3, Idl, Id2, Id3, TR3 (nuclear receptor subfamily 4, group A, member 1), NOT (nuclear receptor subfamily 4 , Group A, member 2), CL 100 / dual specif icit y phosphatase 1, cyclooxygenase-2 (hCox-2), cytochrome P450 4F2 (CYP4F 2), prostaglandin D2 synthase ^ Fatty acid desaturase 1, Fatty acid desa turase 2, cholesterol 25-hydroxy ase, 11-beta-hydroxysteroid dehydrogenase (HSD11), glutamate pyruvate transaminase (GPT) ヽ glycine decarboxy la se, ornithine decarboxylase (ODC), GADD34 / Protein phosphatasel regulatry subunit 15A, carboxypeptidase Z, DKFZp434J214 N Cdk-inhibitor p57KIP2, 13 :-::
WAFl/cycl in-dependent kinase inhibitor 1A (p21, Cipl)、 GEM (GTP binding protein overexpressed in skeletal muse丄 e)、 G0S8/RGS2 (regulator of G-p rotein signalling 2)、 A28 - RGS14p、 BL34/regulator of G - protein signallin g 1、 beta-2-adrenergi c receptor x major group rhinovirus receptor (HRV) / ICAM-1 (CD54)、 HB15/CD83S CD69、 secreted epithelial tumor mucin antigen (MUC1) /CD227、 SLC、 GRO- beta、 amphiregulin (AR)、 heparin- binding EGF-lik e growth factor, KIM0508、 DKFZp434A202N DKFZp564F212、 KIAA0924、 RNU2 (RNA, U2 small nuclear)、 RIGUI/PERl (period homolog 1)、 metallothionein 2A、 IPL/TSSC3 (tumor suppressing subtransferable candidate 3)、 Wnt inh ibitory factor - 1、 APR (ATL- derived PMA - responsive gene) ^ clone 23568, 2 3621， 23795, 23873 and 23874 mRNA、 radiation-inducible immediate-early gene (IEX- 1)、 FABP7 (fatty acid binding protein 7， brain) galanin^ clo ne 23933、 glucose transport er-1 ike protein- III (GLUT3) ^ cytokeratin 15、 CYR61、 IgG Fc binding protein^ GADD45B (growth arrest and DNA - damage - in ducible, beta) STAT induced STAT inhibitor- 3/S0CS-3、 および tumor necro sis factor alpha inducible protein A20 WAFl / cycl in-dependent kinase inhibitor 1A (p21, Cipl), GEM (GTP binding protein overexpressed in skeletal muse 丄 e), G0S8 / RGS2 (regulator of G rotein signaling 2), A28-RGS14p, BL34 / regulator of G- protein signalling g 1, beta-2-adrenergi c receptor x major group rhinovirus receptor (HRV) / ICAM-1 (CD54), HB15 / CD83 S CD69, secreted epithelial tumor mucin antigen (MUC1) / CD227, SLC, GRO-beta , Amphiregulin (AR), heparin-binding EGF-lik e growth factor, KIM0508, DKFZp434A202 N DKFZp564F212, KIAA0924, RNU2 (RNA, U2 small nuclear), RIGUI / PERl (period homolog 1), metallothionein 2A, IPL / TSSC3 (tumor suppressing subtransferable candidate 3), Wnt inh ibitory factor-1, APR (ATL-derived PMA-responsive gene) ^ clone 23568, 2 3621, 23795, 23873 and 23874 mRNA, radiation-inducible immediate-early gene (IEX-1), FABP7 (fatty acid binding protein 7, brain) galanin ^ clo ne 23933, glucose transporter-1 ike protein- III (GLUT3) ^ cytokeratin 1 5, CYR61, IgG Fc binding protein ^ GADD45B (growth arrest and DNA-damage-in ducible, beta) STAT induced STAT inhibitor-3 / S0CS-3, and tumor necrosis factor alpha inducible protein A20
d' ) 以下の遺伝子からなる、アトピー性皮膚炎患者の無疹部における発現レ ベルが健常者の発現レベルに比べて低い指標遺伝子群： CL 100 I dual specif i city phosphatase 1、 cyclooxygenase-2 (hCox- 2)、 T eel丄 receptor delta lo cus、 chorionic gonadotropin beta subunit、 dual specificity phosphatase 2、 c-jun proto oncogene、 c- fos、 WAFl I cycl in-dependent kinase inhibito r 1A (p21, Cipl)、 weel tyrosine kinase^ jun - B、 prostaglandin D2 synthas e、 pleiotrophin、 TR3 (nuclear receptor subfamily 4, group A, member 1)、 ATF3 (activating transcription factor 3〉、 tumor necrosis factor recepto r super family, member 13B、 H2B histone family, member H、 keratin, hair, acidic, 3A、 37 kDa leucine— rich repeat (LRR) protein^ cholesterol 25-h ydroxylase^ SMARCD3、 brain abundant, membrane attached signal protein 1、 SEC24 related gene family, member D (S. cerevisiae) glutathione S-tran sferase M3 (brain)、 Friedreich ataxia^ zinc finger protein 187、 KIAA109 5 protein, AREB6, MLLT10、 ESTs (Accession No. AI829701〉、 collagen, type XIV, alpha 1 (undulin)、 FLJ12280、 amphiregulin (AR)、 ESTs (Accession No. AC004940) molybdenum cofactor synthesis 3、 guanylate binding protein 1, interferon - inducible, 67kDa、 ras homo log gene family, member E、 KIM 0924、 armadillo repeat protein ALEX2、 ETR101、 MIP- 1- alpha、 caspase 3, a poptosis - related cysteine protease (variant beta) N caspase 3, apoptosi s一: related cysteine protease (variant a丄 pha)、 clone 23933、 keratin, hair, acidic, 1、 BL34 / regulator of G— protein signalling 1、 Idl、 BTG2、 G0S3 I Fos- B、 weel tyrosine kinase^ glucose transporter-like protein- III (G LUT3)、 YDD19 proteinN GRO- beta、 serine (or cysteine) proteinase inhibit or, clade I (neuroserpin) , member 1、 GEM (GTP binding protein overexpre ssed in skeletal muscle)、 HB15 / CD83、 N0T、 CD95， FAS、 CD69、 c-myc onco gene、 holocarboxylase synthetase^ zinc finger protein 337、 chromosome c ondensation 1、 heparin— binding EGF - like growth factor^ dermatopontin^ S ERPINE1、 interleukin 6 (interferon, beta 2)、 Prostagrandin D2 Synthetas e 21kD (brain)、 zinc finger protein 36， C3H type-like 1、 CYR61、 IgG Fc binding proteinN protein phosphatase 5， cata丄 ytic subunit^ P311 protein^ GADD45B (growth arrest and DNA-damage- inducible, beta) ADP- ribosyiatio n factor-like 7、 syntaxin 11、 ZFP36 (zinc finger protein 36)、 NDRG fami ly member 4、 APR (ATL— derived PMA- responsive gene) ^ T54 protein^ A28-RG S14p、 rearranged L-myc fusion sequence^ clone 24790、 nuclear receptor s ubfamily 4， group A， member 2、 tumor necrosis factor alpha inducible pr otein A20、 beta— 2 - adrenergic receptor ^ phosphodiesterase 3B、 EGRl (earl y growth response 1)、 およぴ MCP1 d ') An indicator gene group consisting of the following genes, whose expression level in the eruption area of atopic dermatitis patients is lower than that in healthy subjects: CL 100 I dual specifi city phosphatase 1, cyclooxygenase-2 ( hCox-2), Teel 丄 receptor delta locus, chorionic gonadotropin beta subunit, dual specificity phosphatase 2, c-jun proto oncogene, c-fos, WAFl cycl in-dependent kinase inhibito r 1A (p21, Cipl), weel tyrosine kinase ^ jun-B, prostaglandin D2 synthas e, pleiotrophin, TR3 (nuclear receptor subfamily 4, group A, member 1), ATF3 (activating transcription factor 3>, tumor necrosis factor receptor super family, member 13B, H2B histone family , member H, keratin, hair, acidic, 3A, 37 kDa leucine— rich repeat (LRR) protein ^ cholesterol 25-h ydroxylase ^ SMARCD3, brain abundant, membrane attached signal protein 1, SEC24 related gene family, member D (S. cerevisiae) glutathione S-tran sferase M3 (brain), Friedreich ataxia ^ zinc finger protein 187, KIAA109 5 protein, AREB6, MLLT10 , ESTs (Accession No.AI829701>, collagen, type XIV, alpha 1 (undulin), FLJ12280, amphiregulin (AR), ESTs (Accession No.AC004940) molybdenum cofactor synthesis 3, guanylate binding protein 1, interferon-inducible, 67 kDa, ras homo log gene family, member E, KIM 0924, armadillo repeat protein ALEX2, ETR101, MIP-1-alpha, caspase 3, a poptosis-related cysteine protease (variant beta) N caspase 3, apoptosi s-1: related cysteine protease ( variant a 丄 pha), clone 23933, keratin, hair, acidic, 1, BL34 / regulator of G-- protein signaling 1, Idl, BTG2, G0S3 I Fos- B, weel tyrosine kinase ^ glucose transporter-like protein- III (G LUT3), YDD19 protein N GRO-beta, serine (or cysteine) proteinase inh ibit or, clade I (neuroserpin), member 1, GEM (GTP binding protein overexpres ssed in skeletal muscle), HB15 / CD83, N0T, CD95, FAS, CD69, c-myc onco gene, holocarboxylase synthetase ^ zinc finger protein 337, chromosome condensation 1, heparin—binding EGF-like growth factor ^ dermatopontin ^ S ERPINE1, interleukin 6 (interferon, beta 2), Prostagrandin D2 Synthetas e 21kD (brain), zinc finger protein 36, C3H type-like 1, CYR61, IgG Fc binding protein N protein phosphatase 5, cata 丄 ytic subunit ^ P311 protein ^ GADD45B (growth arrest and DNA-damage- inducible, beta) ADP-ribosyiatio n factor-like 7, syntaxin 11, ZFP36 (zinc finger protein 36), NDRG family member 4, APR (ATL—derived PMA-responsive gene) ^ T54 protein ^ A28-RG S14p, rearranged L-myc fusion sequence ^ clone 24790, nuclear receptor s ubfamily 4, group A, member 2, tumor necrosis factor alpha inducible pr otein A20, beta— 2-adrenergic receptor ^ phosphodiesteras e 3B, EGRl (earl y growth response 1), and MCP1
〔2〕 a)の指標遺伝子群力 metalloproteinase (薩)、 type IV collagenase、 cathepsin Z precursor (CTSZ)、 disintegrin-protease^ pro-cathepsin L (ma jor excreted protein MEP)、 skin collagenase^ SPUVE (protease, serine, 2 3)、 Proprotein convertase subtil isin/kexin typelN tissue inhibitor of m etalloproteinasess beta-migrating plasminogen activator inhibitor I、 ェ L-13Ral IFN-beta 2a (IL- 6)、 heparin - binding EGF-like growth factor, G M-CSFR beta、 interleukin 8 (IL8)、 MCP— 1、 EBIl- ligand cheraokine^ SLC、 GR 0- beta、 monocyte chemotactic protein - 2、 CCR1、 lymph node homing recepto r / L- se丄 ectin、 endothelial leukocyte adhesion molecule 1 (ELAM - 1)、 leu kocyte adhesion protein (LFA- 1/Mac - l/pl50， 95 family) beta, TNFAIP6 (turn or necrosis factor, alpha-induced protein 6)、 M130 antigen extracellula r variant / CD163、 CD53 glycoprotein^ T200 leukocyte common antigen (CD 45, LC- A) isoform 1-3、 THY— 1 (CD90)、 leucocyte immunoglobulin- like rece ptor-3 (LIR— 3)、 tenascin- C、 alpha - 1 type XV collagen^ cartilage oligome ric matrix protein (COMP)、 proteoglycan 1、 immunoglobulin lambda light cnain、 Fc—epsi Ion - receptor ga讓 a— chain、 IgG low affinity Fc fragment re ceptor (CD32)、 immunoglobulin heavy constant gamma 3 (G3m marker)、 immu noglobulin kappa constant hemopoietic cell protein - tyrosine kinase (HC K)、 KIAA0687 / AP4K4, ornithine decarboxylase ODC (EC 4· 1· 1. 17)、 phosp holipase A2, group IIA (platelets, synovial fluid)、 nicotinamide N-meth yl transferase (NNMT)、 actin related protein 2/3 complex, subunit IB (41 kD)、 myosin IB、 gamma- iirterferon- inducible protein (IP - 30)、 RAB31、 reg ulator of G- protein signalling 1 (BL34)、 TNRC3、 insulin-like growth fact or binding protein 4 (IGFBP4)、 nel- related protein 2、 neuronal tissue- e nriched acidic protein (NAP— 22)、 DKFZp58600118 / KIAA1199, lysosomal— as sociated mul t i transmembrane protein (LAPTm5)、 KIAA0296、 serum amyloid A 1、 TYRO protein tyrosine kinase binding protein fatty acid binding pro tein homologue (PA- FABP)、 fibrinogen- like 2、 およぴ six transmembrane ep ithelial antigen of the prostate (STEAP)から選^されたいずれかの遺伝子 である 〔1〕 に記載の方法。 (2) Indicator gene group power of a) metalloproteinase (Satsu), type IV collagenase, cathepsin Z precursor (CTSZ), disintegrin-protease ^ pro-cathepsin L (major excreted protein MEP), skin collagenase ^ SPUVE (protease, serine) , 23), Proprotein convertase subtil isin / kexin typel N tissue inhibitor of metalloproteinases s beta-migrating plasminogen activator inhibitor I, D L-13Ral IFN-beta 2a (IL-6), heparin-binding EGF-like growth factor, G M-CSFR beta, interleukin 8 (IL8), MCP-1, EBIl-ligand cheraokine ^ SLC, GR 0-beta, monocyte chemotactic protein-2, CCR1, lymph node homing receptor / L-seectin, endothelial leukocyte adhesion molecule 1 (ELAM-1), leukocyte adhesion protein (LFA-1 / Mac-l / pl50, 95 family) beta, TNFAIP6 (turn or necrosis factor, alpha-induced protein 6), M130 antigen extracellula r variant / CD163 , CD53 glycoprotein ^ T200 leukocyte common antigen (CD 45, LC-A) isoform 1-3, THY-1 (CD90), leucocyte immunoglob ulin- like rece ptor-3 (LIR-3), tenascin-C, alpha-1 type XV collagen ^ cartilage oligome ric matrix protein (COMP), proteoglycan 1, immunoglobulin lambda light cnain, Fc-epsi Ion-receptor ga juice a — Chain, IgG low affinity Fc fragment receptor (CD32), immunoglobulin heavy constant gamma 3 (G3m marker), immu noglobulin kappa constant hemopoietic cell protein-tyrosine kinase (HC K), KIAA0687 / AP4K4, ornithine decarboxylase ODC (EC 4 1.1.17), phosp holipase A2, group IIA (platelets, synovial fluid), nicotinamide N-methyl transferase (NNMT), actin related protein 2/3 complex, subunit IB (41 kD), myosin IB, gamma- iirterferon-inducible protein (IP-30), RAB31, regulator of G-protein signaling 1 (BL34), TNRC3, insulin-like growth fact or binding protein 4 (IGFBP4), nel-related protein 2, neuronal tissue-enriched acidic protein (NAP—22), DKFZp58600118 / KIAA1199, lysosomal—as sociated mul ti transmembrane protein (LAPTm5), KIAA0296, serum amyloid A 1, TYRO protein tyrosine kinase binding protein fatty acid binding pro tein homologue (PA-FABP), fibrinogen-like 2, and six transmembrane ep ithelial antigen of the prostate The method according to [1], which is any gene selected from (STEAP).
〔3〕 aノの 3¾標逾伝ナ 力 cathepsin C、 airway trypsin— like protease^ se rine protease-like protein、 protease M、 tripsinogen IV b— form、 neutroph il gelatinase associated 丄 ipocalin、 squamous cell carcinoma antigen=ser ine protease inhibitor squamous cell carcinoma antigen 2 (SCCA2)、 mono ncyte/neirtrophi丄 e丄 astase inhibitor Λ alpha l~antitrypsinN elaf in inter leukin-/ receptor N inter丄 eukin 4 receptor x platelet-derived endothelial cell growth factor^ pre— B cell enhancing factor (PBEF) alternative ac tivated macrophage specific CC chemokine 1、 lactotransferrin^ melanoma growth stimulatory activity (MGSA) / Gro alpha、 psoriasin (S100A7)、 MR P-8 (S100A8)、 MRP— 14(S100A9)、 CaN19 (S100A2)、 p cadherin、 130-kD pemphig us vulgaris antigen I Desmoglein 3、 desmocollins type 2b、 CD24 signal t ransducer 0A3 antigenic surface determinant / CD47 monocyte/ macrophag e Ig- related receptor MIR— 7 / CD85、 lyn、 protein tyrosine phosphatase, receptor type, E isoforml, tartrate- resistant acid phosphatase type 5、 cholesterol 25— hydroxylase Phospholipid scramblase 1、 manganese supero xide dismutase (EC 1. 15. 1. 1)、 uridine phosphor iase、 aldose reductase- 1 ike peptide^ 2，， 5， oligoaden iate synthetase isoform E16， E18、 2，， 5， ol igoadenylate synthetase 2 isoform p69， p71、 L-kynurenine hydrolase^ pur ine nucleoside phosphorylase (PNP ; EC 2. 4， 2. 1)、 2，， 5， oligoadenyiate sy nthetase-丄 ike (59 kDa isoform)、 cytokeratin 17、 keratin 6A、 keratin 16、 myosin VA (heavy polypeptide 12， niyoxin) N Small proline -: rich protein SP RK、 small proline-rich protein 2 sma丄丄 prol ine— rich protein IB (corni fin) ^ involucrin^ interferon-inducible protein p78 (MX1)、 interferon- in duced 17- kDa/15-kDa protein^ p27， interferon-alpha-inducible protein 27、 regulator of G- protein signall ing 20、 STAT1、 cyclin B、 proto - oncogene ( nt-oa^ beta defensin 2 (HBD2)、 KI 0101、 tumor suppressing subtransf erable candidate 3 (TSSC3)、 heparin binding protein (HBpl7) / FGF - BP1、 および transcobalamin I力ら選択されたいずれかの遺伝子である 〔1〕 に記載 の方法。 (3) a no 3 ¾ 逾 伝 hep cathepsin C, airway trypsin- like protease ^ serine protease-like protein, protease M, tripsinogen IV b-form, neutrophil gelatinase associated 丄 ipocalin, squamous cell carcinoma antigen = ser ine protease inhibitor squamous cell carcinoma antigen 2 (SCCA2), mono ncyte / neirtrophi 丄 e 丄 astase inhibitor Λ alpha l ~ antitrypsin N elaf in inter leukin- / receptor N inter 丄 eukin 4 receptor x platelet-derived endothelial cell growth factor ^ pre — B cell enhancing factor (PBEF) alternative activated macrophage specific CC chemokine 1, lactotransferrin ^ melanoma growth stimulatory activity (MGSA) / Gro alpha, psoriasin (S100A7), MR P-8 (S100A8), MRP—14 (S100A9), CaN19 (S100A2), p cadherin, 130-kD pemphig us vulgaris antigen I Desmoglein 3, desmocollins type 2b, CD24 signal t ransducer 0A3 antigenic surface determinant / CD47 monocyte / macrophag e Ig-related receptor MIR-7 / CD85, lyn, protein tyrosine phosph atase, receptor type, E isoforml, tartrate-resistant acid phosphatase type 5, cholesterol 25- hydroxylase Phospholipid scramblase 1, manganese supero xide dismutase (EC 1.15.1.1), uridine phosphor iase, aldose reductase-1 ike peptide ^ 2 ,, 5, oligoaden iate synthetase isoform E16, E18, 2, 5, 5, ol igoadenylate synthetase 2 isoform p69, p71, L-kynurenine hydrolase ^ purine nucleoside phosphorylase (PNP; EC 2.4, 2.1), 2 ,, 5, oligoadenyiate sy nthetase- 丄 ike (59 kDa isoform), cytokeratin 17, keratin 6A, keratin 16, myosin VA (heavy polypeptide 12, niyoxin) N Small proline-: rich protein SP RK, small proline-rich protein 2 sma 丄 丄 prol ine— rich protein IB (corni fin) ^ involucrin ^ interferon-inducible protein p78 (MX1), interferon- in duced 17-kDa / 15-kDa protein ^ p27, interferon- alpha-inducible protein 27, regulator of G-protein signalling 20, STAT1, cyclin B, proto-oncogene (nt-oa ^ beta defensin 2 (HBD2), KI 0101, tumor suppressing subtransferable candidate 3 (TSSC3), heparin binding The method according to [1], which is any gene selected from protein (HBpl7) / FGF-BP1 and transcobalamin I.
〔4〕 b)の指標遺伝子群が、 cathepsin V、 SERPINB7 (serine (or cysteine) p roteinase inhibitor, clade B (ovalbumin) , member 7)、 cytokeratin 15、 de smin、 extracellular matrix protein 2、 KI 0537、 deoxyribonuclease I-lik e 2 (DNAS1L2) phosphoenolpyruvate carboxykinase (PCK1)、 3- hydroxy - 3- me thylglutaryl coenzyme A synthase^ arylacetamide deacetylaseN ATPase, Cu ++ transporting, alpha polypeptide (ATP7A)ゝ tyrosinase (TYR)、 monoamine oxidase A、 Aldehyde dehydrogenase 5 family, member Al、 alcohol dehydro genase 1A (class I) , alpha polypeptide^ alcohol dehydrogenase 1C (class(4) The indicator genes of b) are cathepsin V, SERPINB7 (serine (or cysteine) protease inhibitor, clade B (ovalbumin), member 7), cytokeratin 15, de smin, extracellular matrix protein 2, KI0537, deoxyribonuclease I-lik e 2 (DNAS1L2) phosphoenolpyruvate carboxykinase (PCK1), 3-hydroxy-3-me thylglutaryl coenzyme A synthase ^ arylacetamide deacetylase N ATPase, Cu ++ transporting, alpha polypeptide (ATP7A) ゝ tyrosinase (TYR), monoamine oxidase A , Aldehyde dehydrogenase 5 family, member Al, alcohol dehydrogenase 1A (class I), alpha polypeptide ^ alcohol dehydrogenase 1C (class
1)， gamma polypeptide degenerative spermatocyte homolog (sphingolipid delta 4 desaturase) x alpha - 2- glycoprotein 1， zincN perilipin、 lipoprot ein lipase^ aldehyde dehydrogenase 3 family, member A2、 Hemoglobin alph a 1， alpha 2 chain、 class I homeoprotein (H0XA9)、 promyelocytic leukemi a zinc finger protein (PLZF) ^ calcium channel, voltage-dependent, alpha1), gamma polypeptide degenerative spermatocyte homolog (sphingolipid delta 4 desaturase) x alpha-2-glycoprotein 1, zinc N perilipin, lipoprot ein lipase ^ aldehyde dehydrogenase 3 family, member A2, Hemoglobin alph a 1, alpha 2 chain, class I homeoprotein (H0XA9), promyelocytic leukemi a zinc finger protein (PLZF) ^ calcium channel, voltage-dependent, alpha
1H subunit、 sodium channel, nonvo丄 tage - gated 1， beta、 LIGl (ortholog o f mouse integral membrane glycoprotein G - 1)、 WFSl (Wolfram syndrome 1)、 progesterone receptor membrane component 2、 peanut - l ike 1 (Drosophi la)、 type 1 angiotensin II receptor, variant 1-5、 EphB6、 betacellul in、 proline rich 4 (lacrimal)、 retinol binding protein 4、 DKFZP434G0310 (hy pothetical protein)、 loricrin DKFZp586H2123、 KIAA0624, DKFZp564D206、 および DKFZp586F1223から選択されたいずれかの遺伝子である 〔1〕 に記載の 方法。 1H subunit, sodium channel, nonvo 丄 tage-gated 1, beta, LIGl (ortholog of mouse integral membrane glycoprotein G-1), WFSl (Wolfram syndrome 1), progesterone receptor membrane component 2, peanut-like 1 (Drosophi la) , Type 1 angiotensin II receptor, variant 1-5, EphB6, betacellul in, proline rich 4 (lacrimal), retinol binding protein 4, DKFZP434G0310 (hy pothetical protein), loricrin DKFZp586H2123, KIAA0624, DKFZp564D206, and DKFZp586F1223.
1 5 ] b〉の指標遺伝子群;^、 kallikreinlN cystatin E/M、 tissue inhibitor o f metalloproteinase 4、 KIAA1775 (MT- protocadherin)、 keratin 18、 keratin1 5] b> indicator genes; ^, kallikreinl N cystatin E / M, tissue inhibitor of metalloproteinase 4, KIAA1775 (MT-protocadherin), keratin 18, keratin
19、 smooth muscle myosin heavy chain 11， isoform SM2、 sciellin (SCEL) N KIAA0353 I desmuslin (intermediate filament protein) N calponinlN protei n - tyrosine - phosphatase Dl、 angiogenin (RNase A family, 5)、 RNase 4、 ca rbonic anhydrase isozyme VI (CA6)、 amylase, alpha 2B; pancreaticN CMP - N-acetylneuraminic acid hydroxylase Aminomethyltransf erase (glycine cl eavage system protein T)、 Cytochrome P450， subfamily II I A, polypeptide 5、 alcohol dehydrogenase IB c丄 ass I) , beta polypeptide^ FABP7 (fatty a cid binding protein 7)、 FABP4 (Fatty acid binding protein 4)、 KIAA0273 I phytanoyl-CoA hydroxylase interacting proteinN apolipoprotein D、 apol ipoprotein E、 hemoglobin, gamma A， gamma G、 hemoglobin, beta mammaglob in 1、 mammaglobin 2、 secretoglobin, family ID, member 2、 delta sleep in ducing peptide, immunoreactor^ beta-catenin-interacting protein ICAT、 G ATA3、 forkhead/winged helix-like transcription factor 7 (FKHL7)、 Inhibi tor of DNA binding 4 (IM)、 Beta-microseminoprotein isoform a (PSP94) , isoform b (PSP57)、 testicular inhibin beta-B~subunitN TM4SF3 (transmemb rane 4 superfamily member 3)、 ITM2A (integral membrane protein 2A)、 cla udin 8、 syndecan 4 (amphig丄 yean, ryudocan) % proteolipid protein 1、 apMl (adipose most abundant gene transcript 1)、 rolactin-inducible proteinゝ HZF9、 skin-specific protein (xp32)、 Crystallin, alpha B、 Hepatocellular carcinoma antigen gene 520、 Purkinje cell protein 4 (PCP4)、 141H5、 eye lin Dl、 TRIM2 (tripartite motif - containing 2)、 metallothionein IV (MTI V)、 transmembrane 4 superfamily member 11 (plasmolipin) N DKFZp434A202、 KIM0471、 KIAA0450, KIAA0633, KIAA0456, Clorf21s および DKFZp761F2014力 ら選択されたいずれかの遺伝子である 〔1〕 に記載の方法。 19, smooth muscle myosin heavy chain 11, isoform SM2, sciellin (SCEL) N KIAA0353 I desmuslin (intermediate filament protein) N calponinl N protein-tyrosine-phosphatase Dl, angiogenin (RNase A family, 5), RNase 4, ca rbonic anhydrase isozyme VI (CA6), amylase, alpha 2B; pancreatic N CMP-N-acetylneuraminic acid hydroxylase Aminomethyltransf erase (glycine cl eavage system protein T), Cytochrome P450, subfamily II IA, polypeptide 5, alcohol dehydrogenase IB c 丄 ass I) , beta polypeptide ^ FABP7 (fatty a cid binding protein 7), FABP4 (fatty acid binding protein 4), KIAA0273 I phytanoyl-CoA hydroxylase interacting protein N apolipoprotein D, apol ipoprotein E, hemoglobin, gamma A, gamma G, hemoglobin, beta mammaglob in 1, mammaglobin 2, secretoglobin, family ID, member 2, delta sleep in reducing peptide, immunoreactor ^ beta-catenin-interacting protein ICAT, G ATA3, forkhead / winged helix-like transcription factor 7 (FKHL7), Inhibitor of DNA b inding 4 (IM), Beta-microseminoprotein isoform a (PSP94), isoform b (PSP57), testicular inhibin beta-B ~ subunit N TM4SF3 (transmemb rane 4 superfamily member 3), ITM2A (integral membrane protein 2A), cla udin 8 , Syndecan 4 (amphig 丄 yean, ryudocan) % proteolipid protein 1, apMl (adipose most abundant gene transcript 1), rolactin-inducible protein ゝ HZF9, skin-specific protein (xp32), Crystallin, alpha B, Hepatocellular carcinoma antigen gene 520 , Purkinje cell protein 4 (PCP4), 141H5, eye lin Dl, TRIM2 (tripartite motif-containing 2), metallothionein IV (MTI V), transmembrane 4 superfamily member 11 (plasmolipin) N DKFZp434A202, KIM0471, KIAA0450, KIAA0633, KIAA0456, Clorf21 s and any one of the genes selected from DKFZp761F2014.
L 6 ] c' )の指標逾伝子群;^、 BTF3 protein homologueN general transcript io n factor I IF, polypeptide 2, 30kDa、 alternative activated macrophage sp ecific CC chemokine 1、 complement component 1， q subcomponent, beta pol ypeptides transforming growth factor, beta receptor III (betaglycan, 30 0kD)、 branched chain alpha-ketoacid dehydrogenase kinase^ ATPase, Ca++ transporting, ubiquitous^ tyrosinase- related protein 1、 histidine ammon ia - lyase、 androgen -; regulated short-chain dehydrogenase/reductase 1、 gap junction protein, beta 3， 31kD (connexin 31)、 KI 0440、 lymphoid -; res r icted membrane protein (LRMP)、 matrilysin ( MP7)、 specific granule prot ein (28 kDa) (SGP28) type I sigma receptor N FK506 binding protein IB, 12, 6 kDa、 Prolactin - Induced Protein^ SET binding factor 1 (SBF1)、 およ ぴ FLJ12525から選択されたいずれかの遺伝子である 〔1〕 に記載の方法。 L 6] c ') index; 伝; BTF3 protein homologue N general transcript ion factor I IF, polypeptide 2, 30 kDa, alternative activated macrophage sp ecific CC chemokine 1, complement component 1, q subcomponent, beta pol ypeptide s transforming growth factor, beta receptor III (betaglycan, 300 kD), branched chain alpha-ketoacid dehydrogenase kinase ^ ATPase, Ca ++ transporting, ubiquitous ^ tyrosinase- related protein 1, histidine ammon ia-lyase, androgen-; regulated short-chain dehydrogenase / reductase 1, gap junction protein, beta 3, 31kD (connexin 31), KI 0440, lymphoid-; res r icted membrane protein (LRMP), matrilysin (MP7), specific granule prot ein (28 kDa) (SGP28) type The method according to [1], which is any gene selected from Isigma receptor N FK506 binding protein IB, 12, 6 kDa, Prolactin-Induced Protein ^ SET binding factor 1 (SBF1), and FLJ12525.
し 7〕 c， )の指標 伝子群;^、 hemoglobin, alpha 1、 sickle cell beta— globin、 beta- globin (HBB)、 A-gamma globins c arb oxype t i das e M、 HCR (a - helix coi led - coil rod homologue) N nuclear receptor subfamily 1， group H, member 2、 ESTs, Moderately similar to 2004399A chromosomal protein^ runt-relat ed transcription factor ί、 および KI 0664 proteinから選択されたいずれ かの遺伝子である 〔1〕 に記載の方法。 7) c,) Index gene group; ^, hemoglobin, alpha 1, sickle cell beta-globin, beta-globin (HBB), A-gamma globin s c arb oxype ti das e M, HCR (a-helix coi led-coil rod homologue) N nuclear receptor subfamily 1, group H, member 2, ESTs, Moderately similar to 2004399A chromosomal protein ^ any gene selected from runt-relat ed transcription factor ί, and KI 0664 protein The method according to [1].
〔8〕 d，）の指標遺伝子群が、 Idl、 BTG2、 zinc finger protein 36, C3H typelike 1、 EGR1 (early growth response 1)、 MIP-l - alpha、 MCP1、 tumor necros is factor receptor superfamily, member 13B、 HB15 / CD83、 CD95, FAS, CD6 9、 T cell receptor delta locus、 caspase 3, apoptosis— related cysteine p rotease、 serine (or cysteine) proteinase inhibitor, clade I (neuroserpi n)， member 1、 SERPINE1、 prostaglandin D2 synthase 21kDa (brain)、 choles terol 25 - hydroxyiase、 glutathione S - transferase M3 (brain)、 protein pho sphatase 5， catalytic subunitゝ phosphodiesterase 3B、 regulator of G - pro tein signalling 16、 heparin - binding EGF -丄 ike growth f actor N pleiotrophi n、 weel tyrosine kinase^ SMARCD3、 IgG Fc binding protein^ chorionic gon adotropin beta subunitN keratin, hair, acidic, 3A、 37 kD leucine— rich repeat (LRR) protein^ brain abundant, membrane attached signal protein 1、 SEC24 related gene family, member D (S. cerevisiae)、 Friedreich at ax ia、 zinc finger protein 187、 zinc finger protein 337、 MLLT10 collagen, type XIV, alpha 1 (undulin)、 molybdenum cof act or synthesis 3、 guanylat e binding protein 1， interferon - iiu ucible， 67kDa、 ras homo log gene fami ly， member E、 armadillo repeat protein ALEX2、 keratin, hair, acidic, 1、 YDD19 proteins chromosome condensation 1、 dermatopontin^ P311 protein^ syntaxin 11、 NDRG family member 4、 rearranged L-myc fusion sequence^ cl one 24790、 KIAA1095 protein, FLJ12280, ESTs (Accession No. AC004940)、 お ょぴ ESTs (Accession Νο· AI829701)から選択されたいずれかの遺伝子である[8] The indicator genes of d,) are Idl, BTG2, zinc finger protein 36, C3H typelike 1, EGR1 (early growth response 1), MIP-l-alpha, MCP1, tumor necros is factor receptor superfamily, member 13B , HB15 / CD83, CD95, FAS, CD69, T cell receptor delta locus, caspase 3, apoptosis—related cysteine protease, serine (or cysteine) proteinase inhibitor, clade I (neuroserpi n), member 1, SERPINE1, prostaglandin D2 synthase 21kDa (brain), choles terol 25-hydroxyiase, glutathione S-transferase M3 (brain), protein pho sphatase 5, catalytic subunit ゝ phosphodiesterase 3B, regulator of G-pro tein signaling 16 , Heparin-binding EGF-丄 ike growth f actor N pleiotrophin, weel tyrosine kinase ^ SMARCD3, IgG Fc binding protein ^ chorionic gon adotropin beta subunit N keratin, hair, acidic, 3A, 37 kD leucine- rich repeat (LRR) protein ^ brain abundant, membrane attached signal protein 1, SEC24 related gene family, member D (S. cerevisiae), Friedreich at axia, zinc finger protein 187, zinc finger protein 337, MLLT10 collagen, type XIV, alpha 1 (undulin), molybdenum cof act or synthesis 3, guanylate binding protein 1, interferon-iiu ucible, 67kDa, ras homo log gene family, member E, armadillo repeat protein ALEX2, keratin, hair, acidic, 1, YDD19 protein s chromosome condensation 1, dermatopontin ^ P3 11 protein ^ syntaxin 11, NDRG family member 4, rearranged L-myc fusion sequence ^ cl one 24790, KIAA1095 protein, FLJ12280, ESTs (Accession No.AC004940), Oyo ESTs (Accession AIο AI829701) Is the gene
〔1〕 に記載の方法。 The method according to [1].
〔9〕 d，）の指標遺伝子群が、 c— jun proto oncogene, jun— B、 c- fos、 G0S3 / F os— B、 c-myc oncogene^ AREB6、 ATF3 (activating transcription factor 3)、 ETR101、 ZFP36 (zinc finger protein 36〉、 GRO-beta, WAFl / cyclin - depende nt kinase inhibitor 1A (p21， Cipl)、 interleukin 6 (interferon, beta 2)、 CL 100 / dual specificity phosphatase 1、 cyclooxygenase-2 (hCox- 2)、 dua 1 specificity phosphatase 2、 holocarboxylase synthetase^ beta— 2 - adrener gic receptor^ BL34 / regulator of G - protein signalling 1、 GEM (GTP bind ing protein overexpressed in skeletal muscle)、 amphiregulin (AR)、 nucle ar receptor subfamily 4， group A， member 2、 TR3 (nuclear receptor subfa 2 1厂—:― J [9] The indicator genes of d,) are c-jun proto oncogene, jun-B, c-fos, G0S3 / Fos-B, c-myconcogene ^ AREB6, ATF3 (activating transcription factor 3), ETR101, ZFP36 (zinc finger protein 36>, GRO-beta, WAFl / cyclin-dependant kinase inhibitor 1A (p21, Cipl), interleukin 6 (interferon, beta 2), CL 100 / dual specificity phosphatase 1, cyclooxygenase-2 (hCox- 2), dua 1 specificity phosphatase 2, holocarboxylase synthetase ^ beta-2-adrenergic receptor ^ BL34 / regulator of G-protein signaling 1, GEM (GTP bind ing protein overexpressed in skeletal muscle), amphiregulin (AR), nucle ar receptor subfamily 4, group A, member 2, TR3 (nuclear receptor subfa 2 1 Factory —: — J
mily 4, group A, member 1)、 N0T、 glucose transporter-like protein- III (G LUT3)、 GADD45B (growth arrest and DNA- damage - inducible, beta)、 tumor ne crosis factor alpha inducible protein A20、 CYR61、 APR (ATL - derived PMA - responsive gene) N ADP-ribosylation factor-like 7、 T54 proteinN H2B hist one family, member H、 clone 23933、 および KIM0924から選択されたいずれ かの遺伝子である 〔1〕 に記載の方法。 mily 4, group A, member 1), N0T, glucose transporter-like protein-III (G LUT3), GADD45B (growth arrest and DNA- damage-inducible, beta), tumor ne crosis factor alpha inducible protein A20, CYR61, APR (ATL-derived PMA-responsive gene) N ADP-ribosylation factor-like 7, T54 protein N H2B hist one family, member H, clone 23933, and KIM0924 Method.
〔1 0〕 遺伝子の発現レベルを、 cDNAの PCRによって測定する 〔1〕 に記載の 検査方法。  [10] The test method according to [1], wherein the expression level of the gene is measured by cDNA PCR.
〔1 1〕 遺伝子の発現レベルを、 指標遺伝子によってコードされる蛋白質の検 出によって測定する 〔1〕 に記載の検査方法。  [11] The test method according to [1], wherein the expression level of the gene is measured by detecting a protein encoded by the indicator gene.
〔1 2〕 指標遺伝子の塩基配列を含むポリヌクレオチド、 またはその相補鎖に 相補的な塩基配列を有する少なくとも 1 5塩基の長さを有するオリゴヌクレオ チドからなる、 アトピー性皮膚炎検査用試薬であって、 指標遺伝子が 〔1〕 に おける a)〜 、 並びに c' )および d' )のいずれかに記載の群から選択されたいず れかの遺伝子であるァトピー性皮膚炎検査用試薬。  [12] An atopic dermatitis test reagent comprising a polynucleotide containing the nucleotide sequence of the indicator gene or an oligonucleotide having a nucleotide sequence complementary to its complementary strand and having a length of at least 15 nucleotides. And a marker for atopic dermatitis, wherein the indicator gene is any one selected from the group described in a) to c) and c ′) and d ′) in [1].
〔1 3〕 指標遺伝子によってコードされる蛋白質のアミノ酸配列を含むぺプチ ドを認識する抗体からなる、 アトピー性皮膚炎検査用試薬であって、 指標遺伝 子が 〔1〕 における a)〜 、 並びに c' )および d' )のいずれかに記載の群から選 択されたいずれかの遺伝子であるァトピ一性皮膚炎検查用試薬。  [13] An atopic dermatitis test reagent comprising an antibody that recognizes a peptide containing the amino acid sequence of the protein encoded by the indicator gene, wherein the indicator genes are a) to a) in [1], and A reagent for detecting atopic dermatitis, which is one of the genes selected from the group described in any of c ′) and d ′).
〔1 4〕 次の工程を含む、 テトピー性皮膚炎の治療薬のスクリーニング方法で あって、 指標遺伝子が 〔1〕 における a；)〜 d)、 並びに c' )および d' )のいずれか に記載の群から選択されたいずれかの遺伝子であるスクリ一ユング方法。  [14] A method for screening for a therapeutic agent for tetopic dermatitis, comprising the following steps, wherein the indicator gene is any of a;) to d), and any one of c ') and d') in [1]. A screening method, which is any gene selected from the group described.
( 1 ) 指標遺伝子を発現する細胞に候補化合物を接触させる工程、  (1) contacting a candidate compound with cells expressing the indicator gene,
( 2 ) 前記遺伝子の発現レベルを測定する工程、  (2) measuring the expression level of the gene,
( 3 ) 侯補化合物を接触させない対照と比較して、 a)群、 。群、 および c' )群 のいずれかの指標遺伝子については前記遺伝子の発現レベルを低下させる
Figure imgf000023_0001
(3) a) group, compared to a control without contact with the candidate compound. Group and c ′) group, the expression level of said gene is reduced.
Figure imgf000023_0001
化合物を、 また b)群、 d)群、 および d' )群のいずれかの指標遺伝子につい ては前記遺伝子の発現レベルを上昇させる化合物を選択する工程  A step of selecting a compound, and for a marker gene of any one of groups b), d) and d '), a compound which increases the expression level of said gene
〔1 5〕 細胞が株化皮膚細胞である 〔1 4〕 に記载の方法。  [15] The method according to [14], wherein the cells are established skin cells.
〔1 6〕 指標遺伝子の塩基配列を含むポリヌクレオチド、 またはその相補鎖に 相補的な塩基配列を有する少なくとも 1 5塩基の長さを有するオリゴヌクレオ チドと、 指標遺伝子を発現する細胞を含む、 アトピー性皮膚炎の治療薬侯補化 合物をスクリーニングするためのキットであって、 指標遺伝子が 〔1〕 におけ る a)〜 、 並びに c )および d' )のいずれかに記載の群から選択されたいずれか の遺伝子であるキット。  [16] an atopy comprising a polynucleotide containing the nucleotide sequence of the indicator gene, or an oligonucleotide having a nucleotide sequence complementary to the complementary strand thereof and having a length of at least 15 nucleotides, and a cell expressing the indicator gene; A kit for screening for a therapeutic compound for atopic dermatitis, wherein the indicator gene is selected from the group described in any of a) to c) and c) and d ') in (1). A kit which is any of the genes described above.
〔1 7〕 指標遺伝子によってコードされる蛋白質のアミノ酸配列を含むぺプチ ドを認識する抗体と、 指標遺伝子を発現する細胞を含む、 アトピー性皮膚炎の 治療薬候補化合物をスクリーニングするためのキットであって、 指標遺伝子が [17] An antibody that recognizes a peptide containing the amino acid sequence of the protein encoded by the indicator gene, and a kit for screening candidate compounds for a therapeutic agent for atopic dermatitis, including cells that express the indicator gene And the indicator gene
〔1〕 における a)〜 、 並びに c' )および d' )のいずれかに記載の群から選択さ れたいずれかの遺伝子であるキット。 A kit which is any one of the genes selected from a) to c) and c ′) and d ′) according to [1].
〔 1 8〕 指標遺伝子または指標遺伝子と機能的に同等な遺伝子の皮膚における 発現強度を上昇させたトランスジエニック非ヒト脊椎動物からなるアトピー性 皮膚炎モデル動物であって、 指標遺伝子が 〔1〕 における a)、 、 および c，：)、 並びに以下の A)または C)に記載の群から選択されたいずれかの遺伝子であるモ ァノレ動物。  [18] An atopic dermatitis model animal comprising a transgenic non-human vertebrate with an increased expression level in the skin of an indicator gene or a gene functionally equivalent to the indicator gene, wherein the indicator gene is [1] A) a mouse animal selected from the group consisting of a),, and c, :), and any one of the groups described in A) or C) below.
A)以下の遺伝子からなる： ダニァレルゲン感作マゥスの耳介皮膚における発 現レベルがダニアレルゲン非感作マウスの耳介皮膚に比べて高い指標遺伝子 群： Cathepsin C、 Matrix metalloproteinase 9、 Granzyme B、 M. musculus 24p 3 gene、 Interleukin I receptor Λ Interleukin 6、 interleukin 4 receptor, alpha、 Mus musculus cDNA /clone=2900006G01 Interleukin 3 receptor, bet a chain 丄、 Smal l inducible cytokine A2、 Macrophage inflammatory protein 2、 monocyte chemoattractant protein - 2 (MCP—2) precursor C emokine (C一 2 3;— — 一 A) Consists of the following genes: Indicator genes whose expression level in the auricle skin of mite allergen-sensitized mice is higher than that of the mite allergen-unsensitized mice Group: Cathepsin C, Matrix metalloproteinase 9, Granzyme B, M musculus 24p 3 gene, Interleukin I receptor Λ Interleukin 6, interleukin 4 receptor, alpha, Mus musculus cDNA / clone = 2900006G01 Interleukin 3 receptor, bet a chain 丄, Small inducible cytokine A2, Macrophage inflammatory protein 2, monocyte chemoattractant protein- 2 (MCP—2) precursor C emokine (C 2 3; — — one
C) receptor 1、 intracellular ca丄 cium- binding protein (MRP8)、 intracellu lar calcium-binding protein (MRP 14) N complement receptor 3 beta subunit MAC— 1、 upl4b05. xls Tumor necrosis factor induced protein 6、 cell surf a ce glycoprotein CD53、 Mus musculus cDNA, 3 end /clone=4732410E23 Tenas cin C、 Mouse proteoglycan core protein^ Mouse beta Fc receptor type II (FCRII)、 Hemopoietic cell kinase^ Mouse mRNA for protein tyrosine phosp hatase epsilon、 ma72f04. xl、 keratin 16、 Small proline - rich protein 2k SPRRlb- protein^ Mus musculus cDNA / clone=2210020E15 Signal transducer and activator of transcription 1、 us musculus cDNA， 3 end /clone=73304 23G02、 および TYRO protein tyrosine kinase binding protein C) receptor 1, intracellular ca丄cium- binding protein (MRP8), intracellu lar calcium-binding protein (MRP 14) N complement receptor 3 beta subunit MAC- 1, upl4b05. Xl s Tumor necrosis factor induced protein 6, cell surf a ce glycoprotein CD53, Mus musculus cDNA, 3 end / clone = 4732410E23 Tenas cin C, Mouse proteoglycan core protein ^ Mouse beta Fc receptor type II (FCRII), Hemopoietic cell kinase ^ Mouse mRNA for protein tyrosine phosp hatase epsilon, ma72f04.xl, keratin 16, Small proline-rich protein 2k SPRRlb- protein ^ Mus musculus cDNA / clone = 2210020E15 Signal transducer and activator of transcription 1, us musculus cDNA, 3 end / clone = 73304 23G02, and TYRO protein tyrosine kinase binding protein
C)以下の遺伝子からなる、 DNFB反復塗布接触性皮膚炎モデルマウスの耳介皮 膚における発現レベルが DNFB反復塗布前のマウスの耳介皮膚に比べて高い指標 遺 1 子群： matrix metalloproteinase 12、 cathepsin Z、 Granzyme B、 proteas e， serine, 18、 lipocalin 2、 tissue inhibitor of metalloproteinase 1、 in ter丄 eui in 4 receptor, alpha、 pre— B— ce丄丄 colony— enhancing factor % epari n binding epidermal growth factor-l ike growth factor λ colony st imulatin g factor 2 receptor, beta 1， 丄 ow - affinity (granulocyte- macrophage)、 chem okine (C- C motif) l igand 3、 MCP - 1、 Macrophage inflammatory protein 2、 C hemokine (C- C) receptor 1、 chemokine (C-X-C motif) ligand 11、 intracell ular calcium-binding protein (MRP8)、 intracellular calcium-binding prot ein (MRP 14) CD163 antigenN CD53、 Lyn cholesterol 25 - hydroxylase、 phos pholipid scramblase 1、 superoxide dismutase 2， mitochondrial^ keratin c omp丄 ex 2， basic, gene 6a、 keratin 16、 small proline - rich protein 1B、 In terferon- stimulated protein 15、 RIKEN cDNA 1700093E07 gene, nel-l ike 2 homolog (chicken)、 lysosomal -associated protein transmembrane 5、 f ibrob last growth factor binding protein 1、 および fibrinogen— like protein 2 〔1 9〕 非ヒト脊椎動物がマウスである 〔1 8〕 に記載のモデル動物。 C) An index consisting of the following genes, whose expression level in the auricle skin of a DNFB repetitively applied contact dermatitis model mouse is higher than that of the mouse auricle skin before the repeated application of DNFB: 1 child group: matrix metalloproteinase 12, cathepsin Z, Granzyme B, proteas e, serine, 18, lipocalin 2, tissue inhibitor of metalloproteinase 1, interter eui in 4 receptor, alpha, pre— B— ce 丄 丄 colony— enhancing factor % epari n binding epidermal growth factor -l ike growth factor λ colony st imulatin g factor 2 receptor, beta 1, owow-affinity (granulocyte- macrophage), chem okine (C-C motif) l igand 3, MCP-1, Macrophage inflammatory protein 2, C hemokine (C-C) receptor 1, chemokine (CXC motif) ligand 11, intracellular calcium-binding protein (MRP8), intracellular calcium-binding protein (MRP 14) CD163 antigen N CD53, Lyn cholesterol 25-hydroxylase, phos pholipid scramblase 1, superoxide dismutase 2, mitochondrial ^ kerat in c omp 丄 ex 2, basic, gene 6a, keratin 16, small proline-rich protein 1B, Interferon-stimulated protein 15, RIKEN cDNA 1700093E07 gene, nel-like 2 homolog (chicken), lysosomal -associated protein transmembrane 5 , F ibrob last growth factor binding protein 1, and fibrinogen—like protein 2 [19] The model animal according to [18], wherein the non-human vertebrate is a mouse.
〔2 0〕 指標遺伝子または指標遺伝子と機能的に同等な遺伝子の皮膚における 発現強度を低下させたトランスジヱニック非ヒト脊椎動物からなるアトピー性 皮膚炎モデル動物であって、 指標遺伝子が 〔1〕 における b)、 d)、 および d' )、 並びに以下の B)または D)に記載の群から選択されたいずれかの遺伝子であるモ アル動物。  [20] An atopic dermatitis model animal comprising a transgenic non-human vertebrate with reduced expression intensity in the skin of an indicator gene or a gene functionally equivalent to the indicator gene, wherein the indicator gene is [1 A) a moral animal which is a gene selected from b), d), and d '), and any one of the groups described in B) or D) below.
B) 以下の遺伝子からなる、 ダニアレルゲン感作マウスの耳介皮膚における発 現レベルがダニアレルゲン非感作マウスの耳介皮膚に比べて低い指標遺伝子 W ： MEP mR A、 sciellin Putative 0rtholog、 Id4 dominant negative helix - 1 oop - helix geneN metal lothionein 4 Putative 0rtholog retinol binding pr otein (RBP)、 および RIKEN cDNA 0610006G05 gene B) An indicator gene consisting of the following genes, whose expression level in the auricle skin of mite allergen-sensitized mice is lower than that of the mite allergen-unsensitized mice. W: MEP mRA, sciellin Putative 0rtholog, Id4 dominant negative helix-1 oop-helix gene N metal lothionein 4 Putative 0rtholog retinol binding protein (RBP), and RIKEN cDNA 0610006G05 gene
D) 以下の遺伝子からなる、 D FB反復塗布接触性皮膚炎モデルマウスの耳介皮 膚における発現レベルが D FB反復塗布前のマウスの耳介皮膚に比べて低い指標 逾 fe子群： keratin comple 1， acidic, gene 1り、 sciellin Putative Ortholo g、 protein tyrosine phosphatase, non-receptor type 21、 expressed sequen ce AW494241、 apolipoprotein D、 GATA binding protein 3、 Id4 dominant neg ative helix-loop-helix gene, RIKEN cDNA 4631434019 gene, CDCREL-1 homol og、 adipocyte complement related protein of 30 kDa、 loricrin^ cDNA, 5' end  D) An index consisting of the following genes, whose expression level in the auricle skin of a DFB repeated application contact dermatitis model mouse is lower than that in the mouse auricle skin before the repeated application of DFB: keratin comple: keratin comple 1, acidic, gene 1, sciellin Putative Ortholog, protein tyrosine phosphatase, non-receptor type 21, expressed sequence AW494241, apolipoprotein D, GATA binding protein 3, Id4 dominant negative helix-loop-helix gene, RIKEN cDNA 4631434019 gene, CDCREL-1 homolog, adipocyte complement related protein of 30 kDa, loricrin ^ cDNA, 5 'end
〔2 1〕 非ヒト脊椎動物がマウスである 〔2 0〕 に記載のモデル動物。  [21] The model animal according to [20], wherein the non-human vertebrate is a mouse.
〔2 2〕 次の i) -iv)のいずれかに記載の成分をマウスに投与する工程を含む、 ァレルギ一性皮膚炎モデル動物の製造方法。  [22] A method for producing an animal model for allergic allergic dermatitis, which comprises a step of administering the component according to any one of the following i) to iv) to a mouse.
i) 〔1 8〕 における A)および C)に記載の遺伝子群から選択されたいずれかの 遺伝子を構成する塩基配列を含むポリヌクレオチド、  i) a polynucleotide comprising a nucleotide sequence constituting any of the genes selected from the group of genes according to A) and C) in (18),
ii) 〔1 8〕 における A)および C)に記載の遺伝子群から選択されたいずれか の遺伝子を構成する塩基配列を含むポリヌクレオチドによってコードされるタ ンパク質 ii) A tag encoded by a polynucleotide containing a nucleotide sequence that constitutes any of the genes selected from the gene groups described in A) and C) in [18]. Protein
iii) 〔2 0〕 における B)および D)に記載の遺伝子群から選択されたいずれか の遺伝子を構成する塩基配列を含むポリヌクレオチドのアンチセンスまたは R A iv) 〔2 0〕 における B)および！)）に記載の遺伝子群から選択されたいずれか の遺伝子を構成する塩基配列を含むポリヌクレオチドによってコードされるタ ンパク質に結合する抗体、 またはその抗原結合領域を含む断片  iii) Antisense or RA of a polynucleotide comprising a nucleotide sequence constituting any of the genes selected from the group of genes described in B) and D) in [20] or RAiv) B) and! )), An antibody that binds to a protein encoded by a polynucleotide containing a nucleotide sequence that constitutes any of the genes selected from the group of genes described in)), or a fragment containing the antigen-binding region thereof.
〔2.3〕 〔2 2〕 における i)-iv)のいずれかに記載の成分を有効成分として含む、 マウスにァレルギ一性皮膚炎を誘導するための誘導剤。  [2.3] An inducer for inducing allergic monodermatitis in mice, comprising the ingredient according to any of i) to iv) in [22] as an active ingredient.
〔2 4〕 次の工程を含む、 アトピー性皮膚炎の治療薬のスクリーニング方法で あって、 指標遺伝子が 〔1〕 における a)〜 、 〔1〕 における c' )および d' )、 (24) A method for screening a therapeutic agent for atopic dermatitis, comprising the following steps, wherein the indicator genes are (a) to (1) in (1), c ′) and d ′) in (1),
〔1 8〕 における A)および C)、 および 〔2 0〕 における B)および D)のいずれ 力に記載の群から選択されたいずれかの遺伝子、 または指標遺伝子と機能的に 同等な遺伝子であるスクリ一ユング方法。 A gene selected from the group described in any of A) and C) in (18) and B) and D) in (20), or a gene functionally equivalent to the indicator gene Screen Jung method.
( 1 ) 被験動物に候補化合物を投与する工程、  (1) administering a candidate compound to a test animal,
( 2 ) 前記被験動物の生体試料における指標遺伝子の発現強度を測定する工程、 (2) measuring the expression intensity of the indicator gene in the biological sample of the test animal,
( 3 ) 侯補化合物を接触させない対照と比較して、 a〉群、 c)群、 c' )群、 A)群、 並びに C〉群の指標遺伝子については前記遺伝子の発現レベルを低下させる 化合物を、 また b)群、 d)群、 d' )群、 B)群、 並びに D)群の指標遺伝子につ いては前記遺伝子の発現レベルを上昇させる化合物を選択する工程、(3) Compounds that reduce the expression levels of the indicator genes of the a> group, c) group, c ′) group, A) group, and C> group as compared to the control not contacted with the candidate compound And b), d), d ′), B), and D) a marker gene that increases the expression level of the gene,
〔2 5〕 次の工程を含む、 ァトピー性皮膚炎の治療薬のスクリ一ユング方法で あって、 指標遺伝子が 〔1〕 における a)〜 、 並びに c' )および d' )のいずれか に記載の群から選択されたいずれかの遺伝子、 または指標遺伝子と機能的に同 等な遺伝子であるスクリーユング方法。 (25) A method for screening a therapeutic agent for atopic dermatitis, comprising the following steps, wherein the indicator gene is any one of a) to) and any one of c ') and d') in (1). The screening method, wherein the gene is a gene selected from the group or a gene functionally equivalent to the indicator gene.
( 1 ) 指標遺伝子の転写調節領域と、 この転写調節領域の制御下に発現するレ ポータ一遺伝子とを含むベクタ一を導入した細胞と候補化合物を接触させ る工程、 (1) A candidate compound is brought into contact with a cell into which a vector containing a transcription regulatory region of an indicator gene and a reporter gene expressed under the control of this transcription regulatory region has been introduced. Process,
( 2 ) 前記レポーター遺伝子の活性を測定する工程、 および  (2) measuring the activity of the reporter gene, and
( 3 ) 侯補化合物を接触させない対照と比較して、 a)群、 c)群、 および ）群 のいずれかの指標遺伝子については前記レポーター遺伝子の発現レベルを 低下させる化合物を、 また b)群、 d)群、 および d' )群のいずれかの指標遺 伝子については前記レポ一タ一遺伝子の発現レベルを上昇させる化合物を 選択する工程、  (3) a compound that reduces the expression level of the reporter gene for any of the indicator genes in groups a), c), and) as compared to a control not contacted with the candidate compound; A) selecting a compound that increases the expression level of the reporter gene for any of the indicator genes of the groups d) and d ′);
〔2 6〕 次の工程を含む、 アトピー性皮膚炎の治療薬のスクリーニング方法で あって、 指標遺伝子が 〔1〕 における a)〜 、 並びに c' )および d' )のいずれか に記載の群から選択された ヽずれかの遺伝子、 または指標遺伝子と機能的に同 等な遺伝子であるスクリ一ユング方法。  (26) A method for screening for a therapeutic agent for atopic dermatitis, comprising the following steps, wherein the indicator gene is any one of a) to) and c ′) and d ′) in (1). Screening method, which is a gene selected from the group or a gene functionally equivalent to the indicator gene.
( 1 ) 指標遺伝子によってコードされる蛋白質と候補化合物を接触させるェ 程、  (1) contacting the candidate compound with the protein encoded by the indicator gene,
( 2 ) 前記蛋白質の活性を測定する工程、 および  (2) measuring the activity of the protein, and
( 3 ) 侯補化合物を接触させない対照と比較して、 a)群、 c)群、 および c' ) 群のいずれかの指標遺伝子については前記活性を低下させる化合物を、 また b)群、 d)群、 および d' )群のいずれかの指標遺伝子については前記 活性を上昇させる化合物を選択する工程  (3) Compared with a control not contacted with a candidate compound, a compound that reduces the activity of any of the indicator genes in groups a), c) and c ′); Selecting a compound that increases the activity for any of the indicator genes of group d) and group d ')
〔2 7〕 〔1 4〕、 〔2 4〕、 〔2 5〕、 および 〔2 6〕 のいずれかに記載のス クリーニング方法によって得ることができる化合物を有効成分として含有する、 ァトピー性皮膚炎の治療薬。  [27] atopic dermatitis, comprising as an active ingredient a compound obtainable by the screening method according to any one of [14], [24], [25] and [26]; Remedy.
〔2 8〕 指標遺伝子、 またはその一部のアンチセンス DNAを有効成分として含 むアトピー性皮膚炎の治療薬であって、 指標遺伝子が 〔1〕 における a)、 c)、 および c' )のいずれかに記載の群から選択されたいずれかの遺伝子である治療薬。 [28] A therapeutic agent for atopic dermatitis containing the indicator gene or a part thereof as an active ingredient, wherein the indicator gene is selected from a), c) and c ') in [1]. A therapeutic agent that is any gene selected from the group described in any of the above.
〔2 9〕 指標遺伝子によってコードされる蛋白質のアミノ酸配列を含むぺプチ ドを認識する抗体を有効成分として含む、 ァトピー性皮膚炎の治療薬であって、 2 7に——— (29) a therapeutic agent for atopic dermatitis, comprising, as an active ingredient, an antibody that recognizes a peptide containing an amino acid sequence of a protein encoded by an indicator gene, 2 7 ———
指標遺伝子が 〔1〕 における a)、 c) s および c )のいずれかに記載の群から選 択されたレヽずれかの遺伝子である治療薬。 A therapeutic agent wherein the indicator gene is any one of the genes selected from the group described in any of a), c) s and c) in [1].
〔3 0〕 指標遺伝子、 または指標遺伝子によってコードされる蛋白質を有効成 分として含む、 アトピー性皮膚炎の治療薬であって、 指標遺伝子が 〔1〕 にお ける b)、 d)、 および d' )のいずれかに記載の群から選択されたいずれかの遺伝 子である治療薬。  [30] A therapeutic agent for atopic dermatitis, comprising an indicator gene or a protein encoded by the indicator gene as an active ingredient, wherein the indicator gene is b), d) and d in [1]. A therapeutic agent which is any of the genes selected from the group described in any of).
[ 3 1〕 指標遺伝子を測定するためのプローブを固定したアトピー性皮膚炎の 診断用 DNAチップであって、 指標遺伝子が 〔1〕 に記載された a)群〜 d)群、 並 ぴに c' )および d' )のいずれかから選択された少なくとも 1種類の遺伝子である DNAチップ。  [31] A DNA chip for diagnosing atopic dermatitis on which a probe for measuring an indicator gene is immobilized, wherein the indicator gene is a) group to d) group described in [1], and DNA chip which is at least one kind of gene selected from any of the following:
あるいは本発明は、 〔1 4〕、 〔2 4〕ゝ 〔2 5〕 および 〔2 6〕 のいずれかに記 載のスクリ一ユング方法によって得ることができる化合物を投与する工程を含 む、 アトピー性皮膚炎の治療方法に関する。 また本発明は、 〔1 4〕、 〔2 4〕、 〔2 5〕 および 〔2 6〕 のいずれかに記載のスクリーニング方法によって得る ことができる化合物の、 ァトピー性皮膚炎の治療用医薬組成物の製造における 使用に関する。  Alternatively, the present invention provides an atopy comprising a step of administering a compound obtainable by the screening method described in any one of [14], [24] 2 [25] and [26]. The present invention relates to a method for treating atopic dermatitis. The present invention also provides a pharmaceutical composition for treating atopic dermatitis, comprising a compound obtainable by the screening method according to any one of [14], [24], [25] and [26]. Use in the manufacture of
加えて本発明は、 次の成分（i)または（ii)を投与する工程を含む、 アトピー性 皮膚炎の治療方法に関する。 あるいは本発明は、 次の成分 (i)または（ii)の、 ァ トビー性皮膚炎の治療用医薬組成物の製造における使用に関する。  In addition, the present invention relates to a method for treating atopic dermatitis, comprising a step of administering the following component (i) or (ii). Alternatively, the present invention relates to the use of the following component (i) or (ii) in the manufacture of a pharmaceutical composition for treating arthro- dermatitis.
(i)上記 a)、 、 または c' こ記載の遺伝子、 またはその一部のアンチセンス 膽、  (i) the above a),, or c 'the gene described herein or a part thereof,
(ii)上記 a)、 c)、 または c' )に記載の遺伝子によってコードされる蛋白質のァ ミノ酸配列を含むぺプチドを認識する抗体  (ii) an antibody that recognizes a peptide containing an amino acid sequence of a protein encoded by the gene according to a), c), or c ′) above
更に本発明は、 次の成分（iii)または（iv)を投与する工程を含む、 アトピー性 皮膚炎の治療方法に関する。 あるいは本発明は、 次の成分（iii)または（iv)の、 ァトピー性皮膚炎の治療用医薬組成物の製造における使用に関する。
Figure imgf000029_0001
Furthermore, the present invention relates to a method for treating atopic dermatitis, comprising a step of administering the following component (iii) or (iv). Alternatively, the present invention relates to the use of the following component (iii) or (iv) in the manufacture of a pharmaceutical composition for treating atopic dermatitis.
Figure imgf000029_0001
(iii)上記 b)、 d)または d，）に記載の遺伝子、  (iii) the gene according to b), d) or d,) above,
(iv)上記 b)、 d)または d' )に記載の遺伝子によってコードされる蛋白質 また本発明は、 以下の乾癬の検査方法、 並びに乾癬治療薬候補化合物のスク リーユング方法に関する。  (iv) The protein encoded by the gene described in b), d) or d ') above. The present invention also relates to the following psoriasis testing methods and screening methods for psoriatic therapeutic drug candidate compounds.
〔3 2〕 次の工程 ( 1 ) 〜 ( 3 ) を含む、 乾癬の検査方法であって、 指標遺伝 子が次の i)〜iv)のいずれかに記載の群から選択されたいずれかの遺伝子である 方法。  (32) A psoriasis testing method, comprising the following steps (1) to (3), wherein the indicator gene is any one selected from the group described in any of the following i) to iv): A method that is a gene.
( 1 ) 被検者の皮疹部および Zまたは無疹部から採取された生体試料における 指標遺伝子の発現レベルを測定する工程  (1) A step of measuring the expression level of an indicator gene in a biological sample collected from a skin eruption and Z or a rash of a subject
( 2 ) 工程 ( 1 ) で測定された発現レベルを、 指標遺伝子が i)または ii)に記 載された遺伝子である場合には、 対照として同じ被検者の無疹部から採取 された生体試料における指標遺伝子の発現レベルと、 また指標遺伝子が ii i)または iv)に記載された遺伝子である場合には、 対照として健常者の生 体試料における指標遺伝子の発現レベルと比較する工程、 およぴ  (2) If the expression level measured in step (1) is the gene described in i) or ii), the expression level measured in step (1) should be the same as the control. Comparing the expression level of the indicator gene in the sample with the expression level of the indicator gene in a biological sample of a healthy subject as a control, if the indicator gene is a gene described in ii i) or iv), Yo
( 3 ) ( 2 ) の比較の結果、 指標遺伝子が i)または iii)に記載された遺伝子の 場合には対照と比較して発現レベルが高い場合に、 また指標遺伝子が ii) または iv)に記載された遺伝子の場合には対照と比較して発現レベルが低 い場合に、 前記被検者は乾癬を有すると判定する工程  (3) As a result of the comparison in (2), when the indicator gene is the gene described in i) or iii), the expression level is higher than that of the control, and when the indicator gene is ii) or iv). Determining that the subject has psoriasis if the expression level of the described gene is low compared to a control
i) 以下の遺伝子からなる、 乾癬の患者において皮疹部における発現レベルが 無珍部に比べて高い指標遺伝子群： cellular retinoic acid binding protein 2、 proteasome (prosome, macropain) activator subunit 2、 interferon indu ced 6 - 16 protein^ heat shock 70kDa protein 4、 flap structure-specific e ndonuclease 1、 NME1、 cycl in-dependent kinase inhibitor 3、 ubiquitin-con jugating enzyme E2C、 calreticulins CDC2 gene、 RAN、 liver arginase (ARG 1)、 connexin 43 (GJAl, Cx43)、 interleukin 1 receptor antagonist ^ ATP-bi nding cassette, sub-family A (ABCl) , member 12、 M— phase phosphoprotein 6、 creatine kinase, mitochondrial 1、 edd4 binding protein 1、 solute ca rrier family 7， member 5、 acid phosphatase, prostate^ plakophilin 1、 UD P glycosyl transferase 1 f mily, polypeptide A4、 ATPase, H+/K+ transport ing, nongastric, alpha polypeptide^ cytoskeleton - associated protein 4、 glucosidase, beta; acid、 interferon— inducible 56 Kd protein、 low densit y lipoprotein receptor N transglutaminase 3、 arachidonate 12-lipoxygenas e, 12R type、 CYP7B1、 tripartite motif-containing 14、 hypothetical prote in FLJ21168、 heme oxygenase ^decycling) 1、 SIOO calcium binding proteini) Indicator genes consisting of the following genes, whose expression level in the rash area is higher in psoriatic patients than in the uncommon area: cellular retinoic acid binding protein 2, proteasome (prosome, macropain) activator subunit 2, interferon induced 6 -16 protein ^ heat shock 70kDa protein 4, flap structure-specific edonuclease 1, NME1, cycl in-dependent kinase inhibitor 3, ubiquitin-con jugating enzyme E2C, calreticulin s CDC2 gene, RAN, liver arginase (ARG 1), connexin 43 (GJAl, Cx43), interleukin 1 receptor antagonist ^ ATP-binding cassette, sub-family A (ABCl), member 12, M-phase phosphoprotein 6, creatine kinase, mitochondrial 1, edd4 binding protein 1, solute carrier family 7, member 5, acid phosphatase, prostate ^ plakophilin 1, UDP glycosyl transferase 1 f mily, polypeptide A4, ATPase, H + / K + transport ing, nongastric , alpha polypeptide ^ cytoskeleton-associated protein 4, glucosidase, beta; acid, interferon- inducible 56 Kd protein, low densit y lipoprotein receptor N transglutaminase 3, arachidonate 12-lipoxygenas e, 12R type, CYP7B1, tripartite motif-containing 14, hypothetical prote in FLJ21168, heme oxygenase ^ decycling) 1, SIOO calcium binding protein
P、 gene from PAC 747L4 SAM domain and HD domain 1、 arylsulfatase F、 p otassium inwardly-rectifying channel, subfamily J, member 15、 BUBl budd ing uninhibited by ben imidazoles 1 homo log beta (yeast) SPllO nuclear body protein isoform b、 guanylate binding protein 1 (GBP1)、 GM2 gangli oside activator protein^ complement factor B preproprotein^ squalene ep oxidase、 solute carrier family 5 (sodium/glucose cotransporter) , memberP, gene from PAC 747L4 SAM domain and HD domain 1, arylsulfatase F, potassium inwardly-rectifying channel, subfamily J, member 15, BUBl budding uninhibited by ben imidazoles 1 homo log beta (yeast) SPllO nuclear body protein isoform b, guanylate binding protein 1 (GBP1), GM2 gangli oside activator protein ^ complement factor B preproprotein ^ squalene ep oxidase, solute carrier family 5 (sodium / glucose cotransporter), member
1、 ZW10 interactor Zwint、 kallikrein 13、 interferon regulatory factor1, ZW10 interactor Zwint, kallikrein 13, interferon regulatory factor
7、 N-myc (and STAT) interactor Stat2、 tripartite motif- containing 22、 kinesin—丄 ike 6、 kallikrein 10N ribonucleotide reductase M2 polypeptide^ chromosome 1 open reading frame 29、 Sjogren syndrome antigen AI、 gamma - glutamyl hydrolase lymphocyte antigen 6 complex, locus E、 interle kin-7, N-myc (and STAT) interactor Stat2, tripartite motif-containing 22, kinesin-- 丄 ike 6, kallikrein 10 N ribonucleotide reductase M2 polypeptide ^ chromosome 1 open reading frame 29, Sjogren syndrome antigen AI, gamma-glutamyl hydrolase lymphocyte antigen 6 complex, locus E, interle kin-
1 receptor antagonist N interferon-induced protein 44、 lectin, galactosi de— binding, soluble, 3 binding proteins retinoblastoma binding protein 6、 vipirin、 interferon— induced protein with tetratricopeptide repeats 4、 SIOO calcium binding protein A12 (calgranulin C)、 bone marrow stroma丄 c ell antigen 2、 chromosome 20 open reading frame 1、 aquaporin 3、 cystati n A (stefin A)、 KIM0186、 retinoblastoma - associated protein HEC、 NSl-as sociated protein 1、 topoisomerase (DNA) II alpha 170kDaN H2A histone fa
Figure imgf000031_0001
1 receptor antagonist N interferon-induced protein 44, lectin, galactosi de--binding, soluble, 3 binding protein s retinoblastoma binding protein 6, vipirin, interferon-- induced protein with tetratricopeptide repeats 4, SIOO calcium binding protein A12 (calgranulin C), bone marrow stroma 丄 cell antigen 2, chromosome 20 open reading frame 1, aquaporin 3, cystatin A (stefin A), KIM0186, retinoblastoma-associated protein HEC, NSl-as sociated protein 1, topoisomerase (DNA) II alpha 170kDa N H2A histone fa
Figure imgf000031_0001
mily, member X、 chemokine exodus - 1、 pituitary tumor- transforming 1、 SCO cytochrome oxidase deficient homo log 2 (yeast) N CDC28 protein kinase r egulatory subunit 2、 kinesin— like 1、 histidine ammonia— lyase、 hypotheti cal protein FLJ10534、 cyclin El、 chromosome 1 open reading frame 34、 ce llular retinoic acid binding protein 2、 TTK protein kinase^ acid phosph atase, prostate^ interleukin 8 receptor beta (IL8RB) s RAB27AN MX2、 thym idine kinase 1、 interferon - inducible 56 Kd protein serum/glucocorticoi d regulated kinase^ EphA2、 nitric oxide synthase 2A、 plasminogen activa tor, tissue type GM2 ganglioside activator protein^ KIAA0963 protein^ kallikrein 13、 ATPase, Class V, type 10B、 GART、 cathepsin C、 airway try psin— like protease^ serine protease-like protein^ protease M、 trypsinog en IV b-form% neutrophil gelatinase associated lipoca丄 in、 squamous cell carcinoma antigen=serine protease inhibitor N squamous cell carcinoma a ntigen 2 (SCCA2)、 mononcyte/neutrophi 1 elastase inhibitor ^ alpha 1— anti trypsin elaf in^ interleukin— 7 receptor ^ interleukin 4 receptor ^ platel et-derived endothelial cell growth factor N pre— B cell enhancing factor (PBEF)、 alternative activated macrophage specific CC chemo ine 1、 lacto transferrins melanoma growth stimulatory activity (MGSA) / Gro alpha、 p soriasin (S100A7)ゝ MRP- 8 (S100A8)、 MRP— 14 (S100A9)、 CaN19 (S100A2)、 p cad herinN 130— kD pemphigus vulgaris antigen I Desmoglein 3、 desmocollins t ype 2b、 CD24 signal transducer^ 0A3 antigenic surface determinant / CD4 7、 monocyte/macrophage Ig-related receptor MIR— 7 / CD85、 lyn、 protein t yrosine phosphatase, receptor type, E isoforml, 2、 "tartrate - resistant ac id phosphatase type 5、 cholesterol 25— hydrox iase、 Phospholipid scrambl ase 1、 manganese superoxide dismutase (EC 1. 15. 1. 1)、 uridine phosphor yl ase aldose reductase— like peptide^ 2，， 5， oligoaden ate synthetase iso
Figure imgf000032_0001
mily, member X, chemokine exodus-1, pituitary tumor-transforming 1, SCO cytochrome oxidase deficient homo log 2 (yeast) N CDC28 protein kinase r egulatory subunit 2, kinesin-like 1, histidine ammonia-lyase, hypotheti cal protein FLJ10534, cyclin El, chromosome 1 open reading frame 34, ce llular retinoic acid binding protein 2, TTK protein kinase ^ acid phosphatase, prostate ^ interleukin 8 receptor beta (IL8RB) s RAB27A N MX2, thym idine kinase 1, interferon-inducible 56 Kd protein serum / glucocorticoi d regulated kinase ^ EphA2, nitric oxide synthase 2A, plasminogen activa tor, tissue type GM2 ganglioside activator protein ^ KIAA0963 protein ^ kallikrein 13, ATPase, Class V, type 10B, GART, cathepsin C, airway try psin- like protease ^ serine protease-like protein ^ protease M, trypsinog en IV b-form % neutrophil gelatinase associated lipoca 丄 in, squamous cell carcinoma antigen = serine protease inhibitor N squamous cell carcinoma a ntigen 2 (SCCA2), mononcyte / neutrophi 1 elastase inhibitor ^ alpha 1-anti trypsin elaf in ^ interleukin-7 receptor ^ interleukin 4 receptor ^ platel et-derived endothelial cell growth factor N pre-B cell enhancing factor (PBEF), alternative activated macrophage specific CC chemo ine 1, lacto transferrins melanoma growth stimulatory activity (MGSA) / Gro alpha, p soriasin (S100A7) ゝ MRP-8 (S100A8), MRP-14 (S100A9), CaN19 (S100A2), p cad herin N 130 — KD pemphigus vulgaris antigen I Desmoglein 3, desmocollins type 2b, CD24 signal transducer ^ 0A3 antigenic surface determinant / CD47, monocyte / macrophage Ig-related receptor MIR — 7 / CD85, lyn, protein tyrosine phosphatase, receptor type, E isoforml, 2, "tartrate-resistant ac id phosphatase type 5, cholesterol 25- hydrox iase, Phospholipid scramblase 1, manganese superoxide dismutase (EC 1.15.1.1), uridine phosphor yl ase aldose reductase- like peptide ^ 2 ,, 5, oligoadenate synt hetase iso
Figure imgf000032_0001
form E16， E18、 2' ， D oligoadenylate synthetase 2 isoform p69， p71、 L-ky nurenine hydrolase^ purine nucleoside p osphorylase (PNP; EC 2. 4, 2, 1)、 2，， 5， oligoadenylate synthetase - like (59 kDa isoform)、 cytokeratin 17、 keratin 6A、 keratin 16、 myosin VA (heavy polypeptide 12， myoxin) N Small pro line-rich protein SPRK、 small pro line-rich protein 2A、 small prolin e - rich protein IB (cornifin) N involucrin^ interferon - inducible protein p78 (MX1)、 interferon- induced 17- kDa/15 - kDa protein^ p27， interferon - al pha - inducible protein 27、 regulator of G- protein signalling 20、 STATU cyclin B、 proto - oncogene (Wnt- 5a)、 beta defensin 2 (HBD2)、 KIM0101、 tu mor suppressing sub tr ansf er ab 1 e candidate 3 (TSSC3)、 heparin binding pr otein (HBpl7) / FGF - BP 1、 およぴ t進 scobalamin I form E16, E18, 2 ', D oligoadenylate synthetase 2 isoform p69, p71, L-ky nurenine hydrolase ^ purine nucleoside p osphorylase (PNP; EC 2.4, 2, 1), 2 ,, 5, oligoadenylate synthetase-like ( 59 kDa isoform), cytokeratin 17, keratin 6A, keratin 16, myosin VA (heavy polypeptide 12, myoxin) N Small pro line-rich protein SPRK, small pro line-rich protein 2A, small prolin e-rich protein IB (cornifin) N involucrin ^ interferon-inducible protein p78 (MX1), interferon- induced 17- kDa / 15-kDa protein ^ p27, interferon-al pha-inducible protein 27, regulator of G-protein signaling 20, STATU cyclin B, proto-oncogene (Wnt-5a), beta defensin 2 (HBD2), KIM0101, tu mor suppressing sub trancer ab 1 e candidate 3 (TSSC3), heparin binding protein (HBpl7) / FGF-BP1, and ぴ t-scobalamin I
ii) 以下の遺伝子からなる、 乾癬の患者において皮疹部における発現レベル が無瘙部に比べて低い指標遺伝子群： actin， alpha 2， smooth muscle, aorta, actin, gamma 2， smooth muscle, enteric^ cisplatin resistance associated^ growth arrest— specific 6、 insulin - like growth factor binding protein 6 (IGFBP6)、 insulin induced protein 1 (INSIG1)、 PDGF receptor beta-like t umor suppressor (PRLTS)、 R- ras、 sarcospan (Kras oncogene- associated gen e)、 fibroblast growth factor (FGF) receptor- 1、 f ibronectin 1 isoform 1 preproprotein% chromosome 21 open reading frame 25、 seven in absentia h omolog 1 (Drosophi丄 aノ、 fatty acid desaturase 1、 fatty acid desaturase 2ヽ Rho- related BTB domain containing 3、 matrilin 2、 adipose specific 2、 LI proteins LIM domain binding 2 I C M1、 myosin light chain kinase (MLC K)、 myosin, light polypeptide 9， regulatory tropomyosin 1 (alpha)、 cys teine-rich protein 1 (intestinal) reversion - inducing- cysteine- rich pro tein with kazal mo"tifs、 amine oxidase, copper containing 3 (vascular ad hesion protein 1)、 cytochrome c oxidase sub unit Vila polypeptide 1 (mus cle)、 chemokine (C- C motif) ligand 14、 ocular development - associated ge ne、 ephrin - B2、 Na, K - ATPase subunit alpha 2 (ATP1A2)、 ATPase, Ca++ trans porting, ubiquitous^ aquaporin 9、 pleiotrophin cadherin 19， type 2、 WN T inhibitory factor 1、 WNTl inducible signaling pathway protein 2、 11— b eta - hydroxys teroi a ehydrogenase (HSD11)、 myelin basic protein (MBP)、 p ro— galanin、 dihydropyrimidinase-like 3、 glypican-4 (GPC4)、 acetylseroto nin 0-niethyltransferase-like synuclein, ga醒 a、 connective tissue growt factor Λ breast cancer anti-estrogen resistance 3、 heat shock 70kDa pr otein 2、 ets variant gene 1、 cAMP - dependent protein kinase subunit RII— beta、 microtubule - associated protein, RP/EB family, member 2、 ATP— bindi ng cassette, sub- family C (CFTR/MRP) 3 member 3、 transmembrane 4 superfa mily member 2、 AXL receptor tyrosine kinase^ phospholamban^ Fc fragment of IgG binding proteins microsomal glutathione S— transferase 3、 DEPP (decidual protein induced by progesterone)、 Arg/Abl - interacting proteinii) An index gene group consisting of the following genes, whose expression level in the rash area is lower than that in the psoriasis area in psoriatic patients: actin, alpha 2, smooth muscle, aorta, actin, gamma 2, smooth muscle, enteric ^ cisplatin resistance associated ^ growth arrest-specific 6, insulin-like growth factor binding protein 6 (IGFBP6), insulin induced protein 1 (INSIG1), PDGF receptor beta-like tumor suppressor (PRLTS), R-ras, sarcospan (Kras oncogene- associated gene e), fibroblast growth factor (FGF) receptor-1, fibronectin 1 isoform 1 preproprotein % chromosome 21 open reading frame 25, seven in absentia h omolog 1 (Drosophi 丄 a, fatty acid desaturase 1, fatty acid desaturase 2ヽ Rho-related BTB domain containing 3, matrilin 2, adipose specific 2, LI protein s LIM domain binding 2 IC M1, myosin light chain kinase (MLC K), myosin, light polypeptide 9, regulatory tropomyosin 1 (alpha), cys teine -rich protein 1 (intestinal) reversion-inducing- cysteine- rich pro tein with kazal mo "tifs, amine oxidase, copper containing 3 (vascular ad hesion protein 1), cytochrome c oxidase sub unit Vila polypeptide 1 (mus cle), chemokine (C-C motif) ligand 14, ocular development-associated gene, ephrin-B2, Na, K-ATPase subunit alpha 2 (ATP1A2), ATPase, Ca ++ trans porting, ubiquitous ^ aquaporin 9, pleiotrophin cadherin 19 , Type 2, WNT inhibitory factor 1, WNTl inducible signaling pathway protein 2, 11-beta-hydroxys teroi a ehydrogenase (HSD11), myelin basic protein (MBP), pro-galanin, dihydropyrimidinase-like 3, glypican-4 (GPC4), acetylseroto nin 0-niethyltransferase-like synuclein, ga a a, connective tissue growt factor Λ breast cancer anti-estrogen resistance 3, heat shock 70kDa protein 2, ets variant gene 1, cAMP-dependent protein kinase subunit RII— beta, microtubule-associated protein, RP / EB family, member 2, ATP--bind ng cassette, sub-family C (CFTR / MRP) 3 member 3, transmembrane 4 superfa mily member 2, AXL receptor tyrosine kinase ^ phospholamban ^ Fc fragment of IgG binding protein s microsomal glutathione S— transfer ase 3, DEPP (decidual protein induced by progesterone), Arg / Abl-interacting protein
ArgBP2a (ArgBP2a)、 H0X2H mRNA from the Hox2 locus, ： frizzled- related pr otein、 G protein-coupled receptor, family C, group 5， member B、 GABA— A receptor pi subunit N mesenchyme homeo box 2 (growth arrest- specific horn eo box)、 keratin 7、 tumor— associated calcium signal transducer 1、 dioxi n- inducible cytochrome P450 (CYP1B1)、 interleukin 1 receptor, type II、 platelet/endothelial cell adhesion molecule (CD31antigen) GRB2- associa ted binding protein 2、 mitogen inducible 2、 transgelinN deleted in live r cancer 1、 8-oxoguanine DNA glycosylase、 enolase 2, (gamma, neuronal) N pinin, desmosome associated proteinN KIAA0367 genes KIAA0280 gene、 KIM 1053 protein. KIAA0729 protein, KIAA1467 protein, KIAA0716 protein, hyp othetical gene CG018、 hypothetical protein FLJ13612, FLJ90798, DKFZp586 11823、 DKFZp5640222、 kallikreinlヽ cystatin E/Mヽ tissue inhibitor of met alloproteinase 4、 KIAA1775 (MT-protocadherin) kera in 18、 keratin 19、 smooth muscle myosin heavy chain 11, isoform SM2、 sciellin (SCEL)、 KIM 0353 I desmuslin (intermediate filament protein) N calponinls protein - ty rosine - phosphatase Dl、 angiogenin (RNase A family, 5)、 RNase 4、 carbon ic anhydrase isozyme VI (CA6)、 amylase, alpha 2B; pancreatic^ CMP— N - ace tylneuraminic acid hydroxylase^ Aminomethyltransf erase (glycine cleavag e system protein T)、 Cytochrome P450, subfamily IIIA, polypeptide 5、 al cohol dehydrogenase IB (class I) , beta polypeptide^ FABP7 (fatty acid b inding protein 7)、 FABP4 (Fatty acid binding protein 4)、 KIAA0273 / phy tanoyl-CoA hydroxylase interacting proteins apolipoprotein D、 apolipopr otein E、 hemoglobin, gamma A, gamma G、 hemoglobin, beta、 mammaglobin 1、 ma讓 aglobin 2、 secretoglobin, family ID, member 2、 delta sleep inducing peptide, immunoreactorN beta - catenin - interacting protein ICAT、 GATA3、 forkhead/winged helix-like transcription factor 7 (FKHL7)、 Inhibitor ofArgBP2a (ArgBP2a), H0X2H mRNA from the Hox2 locus,: frizzled-related pr otein, G protein-coupled receptor, family C, group 5, member B, GABA-A receptor pi subunit N mesenchyme homeo box 2 (growth arrest-specific horn eo box), keratin 7, tumor-- associated calcium signal transducer 1, dioxin-inducible cytochrome P450 (CYP1B1), interleukin 1 receptor, type II, platelet / endothelial cell adhesion molecule (CD31antigen) GRB2- associa ted binding protein 2, mitogen inducible 2, transgelin N deleted in live r cancer 1, 8-oxoguanine DNA glycosylase, enolase 2, (gamma, neuronal) N pinin, desmosome associated protein N KIAA0367 gene s KIAA0280 gene, KIM 1053 protein.KIAA0729 protein, KIAA1467 protein, KIAA0716 protein, hyp othetical gene CG018, hypothetical protein FLJ13612, FLJ90798, DKFZp586 11823, DKFZp5640222, kallikreinl ヽ cystatin E / M ヽ tissue inhibitor of met alloproteinase 4, KIAA1775 (MT-protocadherin) kera in 18, keratin 19, smooth muscle myosin heavy chain 11, isoform SM2, sciellin (SCEL), KIM 0353 I desmuslin (intermediate filament protein) N calponinl s protein-ty rosine-phosphatase Dl , Angiogenin (RNase A family, 5), RNase 4, carbonic anhydrase isozyme VI (CA6), amylase, alpha 2B; pancreatic ^ CMP— N-ace tylneuraminic acid hydroxylase ^ Aminomethyltransf erase (glycine cleavag e system protein T), Cytochrome P450, subfamily IIIA, polypeptide 5, al cohol dehydrogenase IB (class I), beta polypeptide ^ FABP7 (fatty acid b inding protein 7), FABP4 (Fatty acid binding protein 4), KIAA0273 / phy tanoyl-CoA hydroxylase interacting protein s apolipoprotein D, apolipopr otein E, hemoglobin, gamma A, gamma G, hemoglobin, beta, mammaglobin 1, ma sublet aglobin 2, secretoglobin, family ID, member 2, delta sleep inducing peptide, immunoreactor N beta-catenin-interacting protein ICAT, GATA3 , Forkh ead / winged helix-like transcription factor 7 (FKHL7), Inhibitor of
DNA binding 4 (ID4)、 Beta-microseminoprotein isoform a (PSP94) , isofor m b (PSP57)、 testicular inhibin beta-B~subunitx TM4SF3 (transmembrane 4 superfamily member 3)、 ITM2A (integral membrane protein 2A)、 claudin 8、 syndecan 4 (amphiglycan, ryudocan) proteolipid protein 1、 apMl (adipose most abundant gene transcript 1)、 prolactin-inducible protein^ HZF9、 s kin-specific protein (xp32) Crystal 1 in, alpha B、 Hepatocellular carcin oma antigen gene 520、 Purkinje cell protein 4 (PCP4)、 141H5、 cyclin Dl、 TRIM2 (tripartite motif - containing 2)、 metallothionein IV (MTIV)、 trans membrane 4 superfamily member 11 (plasmolipin)、 DKFZp434A202、 KIAA0471、 KIAA0450, KIM0633、 KIAA0456N Clorf21、 および DKFZp761F2014 DNA binding 4 (ID4), Beta-microseminoprotein isoform a (PSP94), isofor mb (PSP57), testicular inhibin beta-B ~ subunit x TM4SF3 (transmembrane 4 superfamily member 3), ITM2A (integral membrane protein 2A), claudin 8, syndecan 4 (amphiglycan, ryudocan) proteolipid protein 1, apMl (adipose most abundant gene transcript 1), prolactin-inducible protein ^ HZF9, skin-specific protein (xp32) Crystal 1 in, alpha B, Hepatocellular carcin oma antigen gene 520, Purkinje cell protein 4 (PCP4), 141H5, cyclin Dl, TRIM2 (tripartite motif - containing 2), metallothionein IV (MTIV), trans membrane 4 superfamily member 11 (plasmolipin), DKFZp434A202, KIAA0471, KIAA0450, KIM0633, KIAA0456 N Clorf21, And DKFZp761F2014
iii) 以下の遺伝子からなる、 乾癬患者の無疹部における発現レベルが健常者 の発現レベルに比べて高い指標遺伝子群： platelet factor 4 (PF4)、 actin, g amma 2， smooth muscle, enter ic interferon valpha, beta and omega) rece ptor 2、 DNA topoisomerase I、 CYP3A4、 eye丄 in- dependent kinase 2、 vascula r endothelial growth factor- D、 ABL1、 adducin 1 (alpha) isoform c、 KLRC3、 RAB2、 l-acylglycerol-3-phosphate 0-acyltransf erase 2、 tryptase, alpha ^ homolog of Yeast RRP4、 MCM3、 hemoglobin, delta, KI 1089、 zinc finger p rotein 44 (KOX 7)、 arylacetamide deacetylase (esterase) synuclein, gam ma、 elastase 2, neutrophil CYP3A5、 FCGR3A (CD16)、 likely ortholog of m ouse neuralin 1、 pyruvate carboxylaseヽ 2， , 5， -o 1 i goad eny late synthetase 1、 muscle RAS oncogene homology butyrophilin, subfamily 3, member A2、 c onnective tissue activation peptide III、 Arg/Abl - interacting protein Ar gBP2、 FLJ33034、 calpain 3、 bleomycin hydrolase^ desmuslin, TAF6レ ESTs (Accession No. AW043812)、 FLJ22269, keratin 7、 scaffold attachment fact or B、 KIM0346、 interferon, alpha - inducible protein 27、 bridging integr ator 1、 smooxh muscle myosin heavy chain hemoglobin, alpha 1、 sickle c e丄 1 beta - globin、 beta-globin (HBB)、 A - gamma globin、 carboxypept i dase M、 HCR (a-nelix coiled - coil rod homologue) x nuclear receptor subfamily 1, group H, member 2、 ESTs, Moderately similar to 2004399A chromosomal pro tein、 runt-related transcription factor 1、 およぴ KIAA0664 protein iii) A group of indicator genes consisting of the following genes, whose expression level in the rash area of psoriatic patients is higher than that in healthy subjects: platelet factor 4 (PF4), actin, g amma 2, smooth muscle, enter ic interferon valpha, beta and omega) receptor 2, DNA topoisomerase I, CYP3A4, eye 丄 in-dependent kinase 2, vascular r endothelial growth factor-D, ABL1, adducin 1 (alpha) isoform c , KLRC3, RAB2, l-acylglycerol-3-phosphate 0-acyltransf erase 2, tryptase, alpha ^ homolog of Yeast RRP4, MCM3, hemoglobin, delta, KI 1089, zinc finger protein 44 (KOX 7), arylacetamide deacetylase (esterase ) synuclein, gamma, elastase 2, neutrophil CYP3A5, FCGR3A (CD16), likely ortholog of mouse neuralin 1, pyruvate carboxylase ヽ 2,, 5, -o 1 i goad eny late synthetase 1, muscle RAS oncogene homology butyrophilin, subfamily 3, member A2, conductive tissue activation peptide III, Arg / Abl-interacting protein Ar gBP2, FLJ33034, calpain 3, bleomycin hydrolase ^ desmuslin, TAF6 ESTs (Accession No.AW043812), FLJ22269, keratin 7, scaffold attachment fact or B, KIM0346, interferon, alpha-inducible protein 27, bridging integrator 1, smooxh muscle myosin heavy chain hemoglobin, alpha 1, sickle ce 丄 1 beta-globin, beta-globin (HBB), A-gamma globin, carboxypept i dase M, HCR (a-nelix coiled-coil rod homologue ) x nuclear receptor subfamily 1, group H, member 2, ESTs, Moderately similar to 2004399A chromosomal pro tein, runt-related transcription factor 1, and KIAA0664 protein
iv) 以下の遺伝子からなる、 乾癬患者の無疹部における発現レベルが健常者 の発現レベルに比べて低い指標遺伝子群： H2B histone family, member G、 cho 丄 inergic receptor, nicotinic, り eta polypeptide 4、 related to the N term inus of tre、 laminin, gamma 2 isoform b、 interleukin 8、 Kruppel - like fa ctor 4 (gut)ヽ Alstrom syndrome 1、 occludin、 c一 jun proto oncogene^ jun - B、 c - fosゝ G0s3 I Fos- Bヽ c- myc oncogeneヽ AREB6 ATF3 (activating transcript ion factor 3)、 ETR101、 ZFP36 (zinc finger protein 36)、 GR0 - beta、 WAF1 I cycl in-dependent kinase inhibitor 1A (p21, Cipl)、 interleukin 6 (inter feron, beta 2)、 CL 100 / dual specificity phosphatase 1、 cyclooxygenas e - 2 (hCox- 2)、 dual specificity phosphatase 2、 holocarboxylase synthetas eヽ beta— 2— adrenergic receptor BL34 I regulator of G— protein signallingiv) An indicator gene group consisting of the following genes, whose expression level in the rash area of psoriasis patients is lower than that in healthy subjects: H2B histone family, member G, cho 丄 inergic receptor, nicotinic, rieta polypeptide 4, related to the N term inus of tre, laminin, gamma 2 isoform b, interleukin 8, Kruppel-like factor 4 (gut) ヽ Alstrom syndrome 1, occludin, c-ichi jun proto oncogene ^ jun -B, c-fos ゝ G0s3 I Fos- B ヽ c- myc oncogene ヽ AREB6 ATF3 (activating transcript ion factor 3), ETR101, ZFP36 (zinc finger protein 36), GR0-beta, WAF1 I cycl in-dependent kinase inhibitor 1A (p21, Cipl), interleukin 6 (inter feron, beta 2), CL 100 / dual specificity phosphatase 1, cyclooxygenas e-2 (hCox-2), dual specificity phosphatase 2, holocarboxylase synthetas e ヽ beta— 2— adrenergic receptor BL34 I regulator of G— protein signaling
1、 GEM (GTP binding protein overexpressed in skeletal muscle)、 amphire gulm (AR)、 nuclear receptor subfamily 4, group A, member 2、 TR3 (nucle ar receptor subfamily 4, group A, member 1)、 N0T、 glucose transporter-li ke protein - III (GLUT3)、 GADD45B (growth arrest and DNA - damage - inducible, beta) s tumor necrosis factor alpha inducible protein A20、 CYR61、 APR (ATL - derived P A-responsive gene) ADP-ribosylation factor-like 7、 T54 protein^ H2B histone family, member H、 clone 23933、 およぴ KIM09241, GEM (GTP binding protein overexpressed in skeletal muscle), amphire gulm (AR), nuclear receptor subfamily 4, group A, member 2, TR3 (nucle ar receptor subfamily 4, group A, member 1), N0T, glucose transporter- liquid protein-III (GLUT3), GADD45B (growth arrest and DNA-damage-inducible, beta) s tumor necrosis factor alpha inducible protein A20, CYR61, APR (ATL-derived P A-responsive gene) ADP-ribosylation factor-like 7, T54 protein ^ H2B histone family, member H, clone 23933, and KIM0924
〔3 3〕 i)の指標遺伝子群力 S、 cellular retinoic acid binding protein 2、 p roteasome (pro some, macropain) activator subunit 2、 interferon induced 6 - 16 protein^ heat shock 70kDa protein 4、 flap structure-specific endon uclease 1、 NME1、 cyclin— dependent kinase inhibitor 3、 ubiquitin-conjuga ting enzyme E2C、 calreticulin^ CDC2 gene、 RA、 liver arginase (ARG1)、 c onnexin 43 (GJAl, Cx43)、 interleukin 1 receptor antagonist^ ATP - binding cassette, sub-family A (ABCl) , member 12、 M- phase phosphoprotein 6、 cr eatine kinase, mitochondrial 1、 edd4 binding protein 1、 solute carrier family 7, member 5、 acid phosphatase, prostate^ plakophilin 1、 UDP gly cosy丄 transferase 1 family, polypeptide A4、 ATPase, H+/K+ transporting, nongastric, alpha polypeptide^ cytoskeleton— associated protein 4、 giuco sidase, beta; acid、 interferon-inducible 56 Kd proteins low density lip oprotein receptor、 transglutaminase 3、 arachidonate 12 - lipoxygenase, 12 R type、 CYP7B1、 tripartite motif-containing 14、 hypothetical protein FL JT21168、 heme oxygenase (decycling) 1、 S100 calcium binding protein P、 g ene from PAC 747L4、 SAM domain and HD domain 1、 arylsulfatase F、 potass 3 6： 一— (3 3) Indicator gene group power of i) S, cellular retinoic acid binding protein 2, proteasome (pro some, macropain) activator subunit 2, interferon induced 6-16 protein ^ heat shock 70kDa protein 4, flap structure-specific endon uclease 1, NME1, cyclin- dependent kinase inhibitor 3, ubiquitin-conjugating enzyme E2C, calreticulin ^ CDC2 gene, RA, liver arginase (ARG1), connexin 43 (GJAl, Cx43), interleukin 1 receptor antagonist ^ ATP-binding cassette , sub-family A (ABCl), member 12, M-phase phosphoprotein 6, creatine kinase, mitochondrial 1, edd4 binding protein 1, solute carrier family 7, member 5, acid phosphatase, prostate ^ plakophilin 1, UDP gly cosy 丄transferase 1 family, polypeptide A4, ATPase, H + / K + transporting, nongastric, alpha polypeptide ^ cytoskeleton- associated protein 4, giuco sidase, beta; acid, interferon-inducible 56 Kd protein s low density lip oprotein receptor, transglutaminase 3, arachidonate 12 -lipoxygena se, 12 R type, CYP7B1, tripartite motif-containing 14, hypothetical protein FL JT21168, heme oxygenase (decycling) 1, S100 calcium binding protein P, gene from PAC 747L4, SAM domain and HD domain 1, arylsulfatase F, potass 3 6: One—
\—一一  \ —11
ium inwardly-rectifying channel, subfamily J， member 15、 BUBl budding u ninhibited by benzimidazoles 1 homolog beta (yeast) s SPllO nuclear body- protein isoform b、 guanylate binding protein 1 (GBP1)、 GM2 ganglioside activator protein^ complement factor B preproprotein^ squalene epoxida se、 solute carrier family 5 (sodium/glucose cotransporter) , member 1、 Z 10 interactor Z intN kallikrein 13、 interferon regulatory factor 7、 N- myc (and STAT) interactor x Stat2、 tripartite motif-containing 22、 kines in-like 6、 kallikrein 10、 ribonucleotide reductase M2 polypeptide^ chro mosome 1 open reading frame 29、 Sjogren syndrome antigen Al、 gamma-glut amyl hydrolase^ lymphocyte antigen 6 complex, locus E、 interleukin— 1 re ceptor antagonist^ interferon - induced protein 44、 lectin, galactoside-b inding, soluble, 3 binding protein、 retinoblastoma binding protein 6、 v ipirin、 interferon - induced protein with tetratricopeptide repeats 4、 SI 00 calcium binding protein A12 (ca丄 granu丄 in C)、 bone marrow stromal eel 1 antigen 2、 chromosome 20 open reading frame 1、 aquaporin 3、 cystatin A (stef in A)、 KI 0186、 retinoblastoma- associated protein HEC、 NSl- asso ciated protein 1、 topoisomerase (DNA) II alpha 170kDa、 H2A histone fami ly， member X、 chemokine exodus— 1、 pituitary tumor-transforming 1、 SCO c ytochrome oxidase deficient homolog 2 (yeast)、 CDC28 protein kinase reg ulatory subunit 、 kinesin - like 1、 histidine a賺 onia— lyase、 hypothetica 1 protein FLJ10534、 cyclin El、 chromosome 1 open reading frame 34、 cell ular retinoic acid binding protein 2、 TTK protein kinase^ acid phosphat ase, prostate^ interleukin 8 receptor beta (IL8RB)、 RAB27A、 X2、 thymid ine kinase 1、 interferon— inducible 56 Kd protein^ serum/glucocorticoid regulated kinase^ EphA2、 nitric oxide synthase 2A、 plasminogen activato r， tissue type、 GM2 ganglioside activator protein^ KIAA0963 proteinN ka 3 7し——ニコ ium inwardly-rectifying channel, subfamily J, member 15, BUBl budding u ninhibited by benzimidazoles 1 homolog beta (yeast) s SPllO nuclear body-protein isoform b, guanylate binding protein 1 (GBP1), GM2 ganglioside activator protein ^ complement factor B preproprotein ^ squalene epoxida se, solute carrier family 5 (sodium / glucose cotransporter), member 1, Z 10 interactor Z int N kallikrein 13, interferon regulatory factor 7, N-myc (and STAT) interactor x Stat2, tripartite motif-containing 22, kines in-like 6, kallikrein 10, ribonucleotide reductase M2 polypeptide ^ chro mosome 1 open reading frame 29, Sjogren syndrome antigen Al, gamma-glut amyl hydrolase ^ lymphocyte antigen 6 complex, locus E, interleukin— 1 re ceptor antagonist ^ interferon- induced protein 44, lectin, galactoside-binding, soluble, 3 binding protein, retinoblastoma binding protein 6, v ipirin, interferon-induced protein with tetratricopeptide repeats 4, SI 00 calcium bind ing protein A12 (ca 丄 granu 丄 in C), bone marrow stromal eel 1 antigen 2, chromosome 20 open reading frame 1, aquaporin 3, cystatin A (stef in A), KI 0186, retinoblastoma-associated protein HEC, NSl-asso ciated protein 1, topoisomerase (DNA) II alpha 170 kDa, H2A histone family, member X, chemokine exodus-1, pituitary tumor-transforming 1, SCO cytochrome oxidase deficient homolog 2 (yeast), CDC28 protein kinase regulatory subunit, kinesin -like 1, histidine a supplement onia- lyase, hypothetica 1 protein FLJ10534, cyclin El, chromosome 1 open reading frame 34, cellular retinoic acid binding protein 2, TTK protein kinase ^ acid phosphatase, prostate ^ interleukin 8 receptor beta (IL8RB ), RAB27A, X2, thymidine kinase 1, interferon- inducible 56 Kd protein ^ serum / glucocorticoid regulated kinase ^ EphA2, nitric oxide synthase 2A, plasminogen activator, tissue type, GM2 ganglioside activator protein ^ KIAA0963 protein N ka 3 7
llikrein 13、 ATPase, Class V， type 10B、 およぴ GARTから選択されたいずれ かの遺伝子である 〔3 2〕 に記載の方法。 The method according to [32], which is any gene selected from llikrein 13, ATPase, Class V, type 10B, and GART.
〔3 4〕 1)の ¾¾ 遺1：∑；子群 ヽ catnepsin Cヽ airway trypsin- like proteaseヽ serine protease-like protein、 protease M、 trypsinogen IV b— form、 neutro phil gelatinase associated丄 ipocalin、 squamous cell carcinoma antigen=s erine protease inhibitor N squamous cell carcinoma antigen 2 (SCCA2) mo noncyte/neutrophil elastase inhibitorヽ alpha 1 -antitrypsin^ elaf in int erleukin-7 receptor interleukin 4 receptor platelet - derived endotheli al cell growth factor pre— B cell enhancing factor (PBEF)、 alternative activated macrophage specific CC chemokine 1、 lactotransferrinN melanom a growth stimulatory activity (MGSA) / Gro alpha、 psoriasin (S100A7)、 M RP-8 (S100A8)、 MRP- 14(S100A9)、 CaN19 (S100A2)、 p cadherin 130- kD pemphi gus vulgaris antigen / Desmoglein 3、 desmocollins type 2b、 CD24 signal transducer^ 0A3 antigenic surface determinant / CD47、 monocyte/ macropha ge Ig - related receptor MIR - 7 / CD85、 lyn、 protein tyrosine phosphatase, receptor type, E isoforml，2、 tartrate— resistant acid phosphatase type 5、 cholesterol 25~hydroxylase Phospholipid scramblase 1、 manganese sup eroxide dismutase (EC 1. 15. 1. 1)、 uridine phosphoryiase、 aldose reductas e- like peptide^ 2' , 5' oligoadenylate synthetase isoform E16， E18、 2，， 5' oligoadenylate synthetase 2 isoform p69， p71、 L-kynurenine hydrolase^ purine nucleoside phosp orylase (PNP ; EC 2. 4. 2. 1)、 2，， 5' oligoadenylate synthetase- like (59 kDa isoform)、 cytokeratin 17、 keratin 6A、 keratin 16、 myosin VA (heavy polypeptide 12, my o in) Small proline- rich protei n SPRK、 small proline - rich protein 2A、 small pro丄 ine-rich protein IB (c ornifin) invo丄 uc:riri、 interferon-inducible protein p78 (MX1)、 interfero n— induced 17— kDa/15— kDa protein^ p27， interferon— alpha— inducible protei
Figure imgf000039_0001
[34] 1) 遺 遺 1: ∑; child group ヽ catnepsin C ヽ airway trypsin-like protease ヽ serine protease-like protein, protease M, trypsinogen IV b-form, neutro phil gelatinase associated 丄 ipocalin, squamous cell carcinoma antigen = serine protease inhibitor N squamous cell carcinoma antigen 2 (SCCA2) mo noncyte / neutrophil elastase inhibitor ヽ alpha 1 -antitrypsin ^ elaf in int erleukin-7 receptor interleukin 4 receptor platelet-derived endotheli al cell growth factor pre— B cell enhancing factor (PBEF), alternative activated macrophage specific CC chemokine 1, lactotransferrin N melanom a growth stimulatory activity (MGSA) / Gro alpha, psoriasin (S100A7), MRP-8 (S100A8), MRP-14 (S100A9), CaN19 (S100A2) ), P cadherin 130- kD pemphi gus vulgaris antigen / Desmoglein 3, desmocollins type 2b, CD24 signal transducer ^ 0A3 antigenic surface determinant / CD47, monocyte / macrophage Ig-related receptor MIR-7 / CD85, lyn, protein tyrosine phosphat ase, receptor type, E isoforml, 2, tartrate- resistant acid phosphatase type 5, cholesterol 25-hydroxylase Phospholipid scramblase 1, manganese superoxide dismutase (EC 1.15.1.1), uridine phosphoryiase, aldose reductas e-like peptide ^ 2 ', 5' oligoadenylate synthetase isoform E16, E18, 2 ,, 5 'oligoadenylate synthetase 2 isoform p69, p71, L-kynurenine hydrolase ^ purine nucleoside phosporylase (PNP; EC 2.4.2.1), 2, , 5 'oligoadenylate synthetase- like (59 kDa isoform), cytokeratin 17, keratin 6A, keratin 16, myosin VA (heavy polypeptide 12, my o in) Small proline-rich protein SPRK, small proline-rich protein 2A, small pro Ine ine-rich protein IB (c ornifin) invo 丄 uc: riri, interferon-inducible protein p78 (MX1), interferon-induced 17—kDa / 15—kDa protein ^ p27, interferon—alpha— inducible protei
Figure imgf000039_0001
n 27、 regulator of G- protein signalling 20、 STATU cyclin B、 proto-onco gene (Wrvt - 5a)、 beta defensin 2 (HBD2)、 IAA0101 tumor suppressing subt ransferable candidate 3 (TSSC3)、 heparin binding protein (HBpl7) / FGF-B Pl、 および transcobalamin Iから選択されたいずれかの遺伝子である 〔3 2〕 に記載の方法。 n 27, regulator of G-protein signaling 20, STATU cyclin B, proto-onco gene (Wrvt-5a), beta defensin 2 (HBD2), IAA0101 tumor suppressing subt ransferable candidate 3 (TSSC3), heparin binding protein (HBpl7) / The method according to [32], which is any gene selected from FGF-B Pl and transcobalamin I.
〔3 5 j ii)の & 遺1 子群カ、 actin, a丄 pha 2， smooth muscle, aorta acti n, gamma 2, smooth muscle, enteric、 cisplatin resistance associated^ gr owth arrest-specific 6、 insulin - like growth factor binding protein 6 (I GFBP6) insulin induced protein 1 (INSIG1)、 PDGF receptor beta-like turn or suppressor (PRLTS) Λ R- ras、 sarcospan (Kras oncogene- associated gene)ヽ fibroblast growth factor (FGF) receptor- 1、 fibronectin 1 isoform 1 prep roprotein chromosome 21 open reading frame 25、 seven in absentia homol og 1 (Drosophila) N fatty acid desaturase 1、 fatty acid desaturase 2、 Rh o- related BTB domain containing 3、 matrilin 2、 adipose specific 2、 LIM protein^ LIM domain binding 2 I CLIM1S myosin light chain kinase (MLCK) N myosin, light polypeptide 9， regulatory^ tropomyosin 1 (alpha)、 cystein e - rich protein 1 (intestinal)、 reversion- inducing - cysteine- rich protein with kazal motifs、 amine oxidase, copper containing 3 (vascular adhesi on protein 1)、 cytochrome c oxidase subunit Vila polypeptide 1 (muscle)ゝ chemokine (C - C motif) ligand 14、 ocular development - associated gene、 ep hrin-B2、 Na， K- ATPase subunit alpha 2 (ATP1A2)、 ATPase, Ca++ transport in g, ubiquitous^ aquaporin 9、 pleiotrophin、 cadherin 19， type 2、 WNT inhi bitory factor 1、 丽 Tl inducible signaling pathway protein 2、 11 - beta- hy droxysteroid dehydrogenase (HSD11)、 myelin basic protein (MBP)、 pro-gal anin、 dihydropyrimidinase-like 3、 glypican-4 (GPC4)、 acetylserotonin 0 - methyl transferase— like、 synuclein, ga讓 a、 connective tissue growth fact
Figure imgf000040_0001
(3 5 j ii) & 1 mosquito group, actin, a 丄 pha 2, smooth muscle, aorta actin, gamma 2, smooth muscle, enteric, cisplatin resistance associated ^ growth arrest-specific 6, insulin-like growth factor binding protein 6 (I GFBP6) insulin induced protein 1 (INSIG1), PDGF receptor beta-like turn or suppressor (PRLTS) Λ R-ras, sarcospan (Kras oncogene- associated gene) ヽ fibroblast growth factor (FGF) receptor- 1, fibronectin 1 isoform 1 preproprotein chromosome 21 open reading frame 25, seven in absentia homol og 1 (Drosophila) N fatty acid desaturase 1, fatty acid desaturase 2, Rh o-related BTB domain containing 3, matrilin 2, adipose specific 2 , LIM protein ^ LIM domain binding 2 I CLIM1 S myosin light chain kinase (MLCK) N myosin, light polypeptide 9, regulatory ^ tropomyosin 1 (alpha), cystein e-rich protein 1 (intestinal), reversion- inducing-cysteine-rich protein with kazal motifs, amine oxidase, copper containing 3 (vascular adhesi on pr otein 1), cytochrome c oxidase subunit Vila polypeptide 1 (muscle) ゝ chemokine (C-C motif) ligand 14, ocular development-associated gene, ephrin-B2, Na, K-ATPase subunit alpha 2 (ATP1A2), ATPase, Ca ++ transport in g, ubiquitous ^ aquaporin 9, pleiotrophin, cadherin 19, type 2, WNT inhi bitory factor 1, 丽 Tl inducible signaling pathway protein 2, 11-beta-hydroxysteroid dehydrogenase (HSD11), myelin basic protein (MBP), pro-gal anin, dihydropyrimidinase-like 3, glypican-4 (GPC4), acetylserotonin 0-methyl transferase— like, synuclein, ga sub a, connective tissue growth fact
Figure imgf000040_0001
or、 breast cancer anti-estrogen resistance 3、 heat shock 70kDa protein 2、 ets variant gene 1、 cAMP— dependent protein kinase subunit RII— beta、 microtubule - associated protein, RP/EB family, member 2、 ATP - binding cas sette, sub-family C (CFTR/MRP) , member 3、 transmembrane 4 superfamily ember 2、 AXL receptor tyrosine inases phospholamban^ Fc fragment of Ig G binding protein^ microsomal glutathione S— transferase 3、 DEPP (decidu a丄 protein induced by progesterone) N Arg/Abl - interacting protein ArgBP2 a (ArgBP2a)、 H0X2H mRNA from the Hox2 locus、 frizzled- related protein^ G protein-coupled receptor, family C， group 5， member B、 GABA— A recepto r pi subunit、 mesenchyme homeo box 2 (growth arrest - specific homeo box) ^ keratin 7、 tumor - associated calcium signal transducer 1、 dioxin-inducib 丄 e cytochrome P450 (CYP1B1)、 interleukin 1 receptor, type II、 platelet/ endothelial cell adhesion molecule (CD31 antigen) GRB2— associated bindi ng protein 2、 mitogen inducible 2、 transgelin、 deleted in liver cancer 1、 8-oxoguanine DNA glycosylase、 enolase 2, (gamma, neuronal) pinin, d esmosome associated proteinN KIAA0367 gene、 KIAA0280 gene、 KIAA1053 pro tein、 KIAA0729 protein, KIAA1467 proteinN KIAA0716 protein, hypothetica 1 gene CG018、 hypothetical protein FLJ13612、 FLJ90798, DKFZp586I1823、 および DKFZp5640222から選択されたいずれかの遺伝子である 〔3 2〕 に記載の 方法。 -or, breast cancer anti-estrogen resistance 3, heat shock 70kDa protein 2, ets variant gene 1, cAMP—dependent protein kinase subunit RII—beta, microtubule-associated protein, RP / EB family, member 2, ATP-binding cas sette, sub-family C (CFTR / MRP), member 3, transmembrane 4 superfamily ember 2, AXL receptor tyrosine inase s phospholamban ^ Fc fragment of Ig G binding protein ^ microsomal glutathione S— transferase 3, DEPP (decidu a 丄 protein induced by progesterone ) N Arg / Abl-interacting protein ArgBP2a (ArgBP2a), H0X2H mRNA from the Hox2 locus, frizzled-related protein ^ G protein-coupled receptor, family C, group 5, member B, GABA—A receptor r pi subunit, mesenchyme homeo box 2 (growth arrest-specific homeo box) ^ keratin 7, tumor-associated calcium signal transducer 1, dioxin-inducib 丄 e cytochrome P450 (CYP1B1), interleukin 1 receptor, type II, platelet / endothelial cell adhesion molecule (CD31 antigen) ) GRB2—associated bi ndi ng protein 2, mitogen inducible 2, transgelin, deleted in liver cancer 1, 8-oxoguanine DNA glycosylase, enolase 2, (gamma, neuronal) pinin, desmosome associated protein N KIAA0367 gene, KIAA0280 gene, KIAA1053 pro tein, KIAA0729 protein , KIAA1467 protein N KIAA0716 protein, hypothetica 1 gene CG018, hypothetical protein FLJ13612, FLJ90798, DKFZp586I1823, and DKFZp5640222. -
〔3 6〕 ii)の指標遺伝子群が、 kallikreinl、 cystatin E/M、 tissue inhibito r of metalloproteinase 4、 KIAA1775 (MT-protocadherin) N keratin 18、 kera tin 19、 smooth muscle myosin heavy chain 11， isoform SM2、 sciellin (Sufi L) N KIAA0353 / desmuslin (intermediate filament protein) N calponinlN pr otein— tyrosine— phosphatase Dl、 angiogenin (RNase A family, 5)、 R ase 4、 carbonic anhydrase isozyme VI (CA6)、 amylase, alpna 2B; pancreaticN CM ー (36) The indicator genes of ii) are kallikreinl, cystatin E / M, tissue inhibitor of metalloproteinase 4, KIAA1775 (MT-protocadherin) N keratin 18, kera tin 19, smooth muscle myosin heavy chain 11, isoform SM2, sciellin (Sufi L) N KIAA0353 / desmuslin (intermediate filament protein) N calponinl N protein— tyrosine— phosphatase Dl, angiogenin (RNase A family, 5), Rase 4, carbonic anhydrase isozyme VI (CA6), amylase, alpna 2B ; pancreatic N CM ー
P-N-acetylneuraminic acid hydroxylase^ Aminomethyltransf erase (glycine cleavage system protein T)、 Cytochrome P450, subfamily IIIA, polypeptid e 5、 alcohol dehydrogenase IB (class 1)， beta polypeptide^  P-N-acetylneuraminic acid hydroxylase ^ Aminomethyltransf erase (glycine cleavage system protein T), Cytochrome P450, subfamily IIIA, polypeptid e 5, alcohol dehydrogenase IB (class 1), beta polypeptide ^
FABP7 (fatty acid binding protein 7)、 FABP4 (Fatty acid binding proteinFABP7 (fatty acid binding protein 7), FABP4 (Fatty acid binding protein 7)
4)、 KIAA0273 / phytanoyl-CoA hydroxylase interacting protein^ apol ipop rotein D、 apolipoprotein E、 hemoglobin, gamma A， gamma G、 hemoglobin, b eta、 mammaglobin 1、 mammaglobin 2、 secretoglobin, family ID, member 2、 delta sleep inducing peptide, immunoreactors beta - catenin - interacting p rotein ICAT、 GATA3、 f orkh e ad/wi nge d hel ix-like transcription factor 7 (FKHL7)、 Inhibitor of DNA binding 4 (ID4) N Beta-microseminoprotein isof orm a (PSP94) , isoform b (PSP57)、 testicular inhibin beta- B- subunit、 TM 4SF3 (transmembrane 4 superfamily member 3)、 ITM2A (integral membrane p rotein 2A)、 claudin 8、 syndecan 4 (amphiglycan, ryudocan) s proteolipid protein 1、 apMl (adipose most abundant gene transcript 1)、 prolactin— ind ucible protein HZF9、 skin-specific protein (xp32)、 Crystallin, alpha B、 Hepatocellular carcinoma antigen gene 520、 Purkinje cell protein 4 (PCP 4)、 141H5、 cyclin Dl、 TRIM2 (tripartite motif-containing 2)、 metal lothi one in IV (MTTV)、 transmembrane 4 superfamily member 11 (plasmolipin)、 D KFZp434A202、 KIM0471、 KIAA0450, KIAA0633, KIAA0456, Clorf21、 および DKF Zp761F2014から選択された 、ずれかの遺伝子である 〔3 2〕 に記載の方法。 4), KIAA0273 / phytanoyl-CoA hydroxylase interacting protein ^ apol ipop rotein D, apolipoprotein E, hemoglobin, gamma A, gamma G, hemoglobin, beta, mammaglobin 1, mammaglobin 2, secretoglobin, family ID, member 2, delta sleep inducing peptide, immunoreactor s beta-catenin-interacting protein ICAT, GATA3, fork ead / winge d helix-like transcription factor 7 (FKHL7), Inhibitor of DNA binding 4 (ID4) N Beta-microseminoprotein isof orm a ( PSP94), isoform b (PSP57), testicular inhibin beta- B-subunit, TM4SF3 (transmembrane 4 superfamily member 3), ITM2A (integral membrane protein 2A), claudin 8, syndecan 4 (amphiglycan, ryudocan) s proteolipid protein 1 , ApMl (adipose most abundant gene transcript 1), prolactin- ind ucible protein HZF9, skin-specific protein (xp32), Crystallin, alpha B, Hepatocellular carcinoma antigen gene 520, Purkinje cell protein 4 (PCP 4), 141H5, cyclin Dl , TRIM2 (tripartite motif-containing 2), metal lothi one in IV (MTTV), transmembrane 4 superfamily member 11 (plasmolipin), D KFZp434A202, KIM0471, KIAA0450, KIAA0633, KIAA0456, Clorf21, and DKF Zp761F2014. the method of.
〔3 7〕 ii i)の指標遺伝子群が、 platelet factor 4 (PF4)、 act in, gamma 2， smooth muscle， enteric^ interferon (alpha, beta and omega) receptor 2、 DNA topoisomerase I、 CYP3A4、 cyclin— dependent kinase 2、 vascular endoth el ial growth factor- D、 ABL1、 adducin 1 (alpha) i soform c、 KLRC3、 RAB2、 1一 acylglycerol - 3 - phosphate 0-acy上 transferase 2、 tryptase, alpha、 homolo g of Yeast RRP4、 MCM3、 hemoglobin, deltaヽ KIAA1089、 zinc finger protein W [37] ii i) The indicator genes are platelet factor 4 (PF4), actin, gamma 2, smooth muscle, enteric ^ interferon (alpha, beta and omega) receptor 2, DNA topoisomerase I, CYP3A4, cyclin— dependent kinase 2, vascular endothial growth factor- D, ABL1, adducin 1 (alpha) isoform c, KLRC3, RAB2, 1 acylglycerol-3-phosphate 0-acy on transferase 2, tryptase, alpha, homolog of yeast RRP4, MCM3, hemoglobin, delta ヽ KIAA1089, zinc finger protein W
4 1「 J 4 1 "J
44 (KOX 7)、 arylacetamide deacetylase (esterase)、 synuclein, ga讓 a、 el astase 2， neutrophil, CYP3A5、 FCGR3A (CD16)、 likely ortholog of mouse n euralin 1、 pyruvate carboxylase^ 2'， 5， -oligoadenylate synthetase 1、 mus cle RAS oncogene homology butyrophi丄 in, subfamily 3, member A2、 connect ive tissue activation peptide III、 Arg/Abl - interacting protein ArgBP2、 FLJ"33034、 calpain 3、 bleomycin hydrolase^ desmuslin、 TAF6LN ESTs (Access ion No. AW043812)、 FLJ22269、 keratin 7、 scaffold attachment factor B、 K IAA0346、 interferon, alpha - inducible protein 27、 bridging integrator 1、 およぴ smooth muscle myosin heavy chainから選択されたいずれかの遺伝子で ある 〔3 2〕 に記載の方法。 44 (KOX 7), arylacetamide deacetylase (esterase), synuclein, ga suba, el astase 2, neutrophil, CYP3A5, FCGR3A (CD16), likely ortholog of mouse neuralin 1, pyruvate carboxylase ^ 2 ', 5, -oligoadenylate synthetase 1, muscle RAS oncogene homology butyrophi 丄 in, subfamily 3, member A2, connective tissue activation peptide III, Arg / Abl-interacting protein ArgBP2, FLJ "33034, calpain 3, bleomycin hydrolase ^ desmuslin, TAF6L N ESTs (Access ion No.AW043812), FLJ22269, keratin 7, scaffold attachment factor B, K IAA0346, interferon, alpha-inducible protein 27, bridging integrator 1, and smooth muscle myosin heavy chain (3) 2].
〔3 8〕 iii)の指標遺伝子群が、 hemoglobin, alpha 1、 sickle cell beta - glo bin、 beta - globin (HBB)、 A-garama globin、 carboxypeptidase M、 HCR (a-heli x coiled- coil rod homologue)、 nuclear receptor subfamily 1, group H, me mber 2、 ESTs, Moderately similar to 2004399A chromosomal protein^ runt- related transcription factor 1、 およぴ KIM0664 proteinから選択されたい ずれかの遺伝子である 〔3 2〕 に記載の方法。  (38) The indicator genes of iii) are hemoglobin, alpha 1, sickle cell beta-glo bin, beta-globin (HBB), A-garama globin, carboxypeptidase M, HCR (a-heli x coiled- coil rod homologue) ), Nuclear receptor subfamily 1, group H, member 2, ESTs, Moderately similar to 2004399A chromosomal protein ^ runt-related transcription factor 1, and KIM0664 protein The described method.
〔3 9〕 iv)の指標遺伝子群が、 H2B histone family, member G、 cholinergic receptor, nicotinic, beta po丄 ypeptide 4、 related to the N terminus of t re、 laminin, gamma 2 isoform b、 interleukin 8、 Kruppel- like factor 4 (g ut)、 Alstrom syndrome 1、 およぴ occludin から選択されたいずれかの遺伝子 である 〔3 2〕 に記載の方法。  (39) The indicator genes of (iv) are H2B histone family, member G, cholinergic receptor, nicotinic, beta po 丄 ypeptide 4, related to the N terminus of tr, laminin, gamma 2 isoform b, interleukin 8, Kruppel -The method according to [32], which is any gene selected from like factor 4 (gut), Alstrom syndrome 1, and occludin.
〔4 0〕 iv)の指標遺伝子群が、 C- jun proto oncogene, jun- B、 c- fos、 G0S3 I (40) The indicator genes of iv) are C-jun proto oncogene, jun-B, c-fos, G0S3 I
Fos- B、 c-myc oncogene^ AREB6、 ATF3 (activating transcription factor 3)、 ETR101、 ZFP36 (zinc finger protein 36)、 GRO- betaヽ WAFl / cyclin- depende nt kinase inhibitor 1A (p21, Cipl)、 interleukin 6 (interferon, beta 2)、 CL 100 I dual specificity phosphatase 1、 cyclooxygenase-2 (hCox— 2)、 dua 1 specificity phosphatase 2、 holocarboxylase synthetase^ beta - 2 - adrener gic receptor ^ BL34 / regulator of G - protein signalling 1、 GEM (GTP bind ing protein overexpressed in skeletal muscle)、 amphiregulin (AR)、 nucle ar receptor subfamily 4, group A, member 2、 TR3 (nuclear receptor subfa mily 4， group A, member 1)、 N0T、 glucose transporter-like protein - III (G LUT3)、 GADD45B (growth arrest and DNA- damage - inducible, beta) tumor ne crosis factor alpha inducible protein A20、 CYR61、 APR (ATL - derived PMA - responsive gene) ADP-ribosylation factor-like 7、 T54 protein^ H2B hist one family, member H、 clone 23933、 および KIM0924から選択されたいずれ かの遺伝子である 〔3 2〕 に記載の方法。 Fos-B, c-myc oncogene ^ AREB6, ATF3 (activating transcription factor 3), ETR101, ZFP36 (zinc finger protein 36), GRO-beta ヽ WAFl / cyclin-dependent kinase inhibitor 1A (p21, Cipl), interleukin 6 (interferon, beta 2), CL 100 I dual specificity phosphatase 1, cyclooxygenase-2 (hCox-2), dua 1 specificity phosphatase 2, holocarboxylase synthetase ^ beta-2-adrenergic receptor ^ BL34 / regulator of G-protein signaling 1, GEM (GTP bind ing protein overexpressed in skeletal muscle), amphiregulin (AR), nucle ar receptor subfamily 4, group A, member 2, TR3 (nuclear receptor subfa mily 4, group A, member 1), N0T, glucose transporter-like protein-III (G LUT3), GADD45B (growth arrest and DNA- damage-inducible, beta) tumor ne crosis factor alpha inducible protein A20, CYR61, APR (ATL-derived PMA-responsive gene) ADP-ribosylation factor-like 7, T54 protein ^ H2B hist one family, member H, clone 23933, or any of the genes selected from KIM0924 The method according to [32].
〔4 1〕 遺伝子の発現レベルを、 cDNAの PCRによって測定する 〔3 2〕 に記載 の検査方法。  [41] The test method according to [32], wherein the expression level of the gene is measured by cDNA PCR.
〔4 2〕 遺伝子の発現レベルを、 指標遺伝子によってコードされる蛋白質の検 出によって測定する 〔3 2〕 に記載の検査方法。  [42] The test method of [32], wherein the expression level of the gene is measured by detecting a protein encoded by the indicator gene.
〔4 3〕 指標遺伝子の塩基配列を含むポリヌクレオチド、 またはその相補鎖に 相補的な塩基配列を有する少なくとも 1 5塩基の長さを有するオリゴヌクレオ チドからなる、 乾癬検査用試薬であって、 指標遺伝子が 〔3 2〕 における i)〜i V)の 、ずれかに記載の群から選択された 1/、ずれかの遺伝子である乾癬検查用試  [43] a psoriasis test reagent comprising a polynucleotide containing the nucleotide sequence of the indicator gene or an oligonucleotide having a nucleotide sequence complementary to its complementary strand and having a length of at least 15 nucleotides, A psoriasis test for a gene whose gene is 1 / selected from the group described in any of the above (i) to (i) in (32).
〔4 4〕 指標遺伝子によってコードされる蛋白質のアミノ酸配列を含むぺプチ ドを認識する抗体からなる、 乾癬検査用試薬であって、 指標遺伝子が 〔3 2〕 における i)〜； ίν)のいずれかに記載の群から選択されたいずれかの遺伝子である [44] A psoriasis test reagent comprising an antibody recognizing a peptide containing an amino acid sequence of a protein encoded by an indicator gene, wherein the indicator gene is any of i) to 〜ν) in [32]. Any of the genes selected from the group described in
〔4 5〕 次の工程を含む、 乾癬の治療薬のスクリーニング方法であって、 指標 遺伝子が 〔3 2〕 における i；)〜 iv)のいずれかに記載の群から選択されたいずれ かの遺伝子であるスクリーニング方法。 ( 1 ) 指標遺伝子を発現する細胞に候補化合物を接触させる工程、 [45] A method for screening a therapeutic agent for psoriasis, comprising the following steps, wherein the indicator gene is any one of the genes selected from the group described in any one of i;) to iv) in [32]. Screening method. (1) contacting a candidate compound with cells expressing the indicator gene,
( 2 ) 前記遺伝子の発現レベルを測定する工程、  (2) measuring the expression level of the gene,
( 3 ) 候補ィヒ合物を接触させない対照と比較して、 i)群または iii)群の指標遺 伝子については前記遺伝子の発現レベルを低下させる化合物を、 また ii)群また は iv)群の指標遺伝子については前記遺伝子の発現レベルを上昇させる化合物を 選択する工程  (3) A compound that decreases the expression level of the gene for the indicator gene of group i) or iii), and ii) or iv) as compared to the control not contacted with the candidate eh. Selecting, for a group of indicator genes, a compound that increases the expression level of said genes
〔4 6〕 細胞が株化皮膚細胞である 〔4 5〕 に記載の方法。  [46] the method of [45], wherein the cells are cell lines;
〔4 7〕 指標遺伝子の塩基配列を含むポリヌクレオチド、 またはその相補鎖に 相補的な塩基配列を有する少なくとも 1 5塩基の長さを有するオリゴヌクレオ チドと、 指標遺伝子を発現する細胞を含む、 乾癬の治療薬侯補化合物をスクリ 一ユングするためのキットであって、 指標遺伝子が 〔3 2〕 における i〉〜iv)の いずれかに記載の群から選択されたいずれかの遺伝子であるキット。  [47] a psoriasis comprising a polynucleotide comprising the nucleotide sequence of the indicator gene, or an oligonucleotide having a nucleotide sequence complementary to the complementary strand thereof and having a length of at least 15 nucleotides, and cells expressing the indicator gene A kit for screening a therapeutic drug candidate compound according to (1), wherein the indicator gene is any gene selected from the group described in any one of (i) to (iv) in [32].
〔4 8〕 指標遺伝子によってコードされる蛋白質のァミノ酸配列を含むぺプチ ドを認識する抗体と、 指標遺伝子を発現する細胞を含む、 乾癬の治療薬候補化 合物をスクリーニングするためのキットであって、 指標遺伝子が 〔3 2〕 にお ける i)〜： Lv)のいずれかに記載の群から選択されたいずれかの遺伝子であるキッ o  [48] An antibody recognizing a peptide containing the amino acid sequence of the protein encoded by the indicator gene, and a kit for screening a candidate drug for treating psoriasis, including cells expressing the indicator gene. The indicator gene is a kit selected from the group described in any one of i) to Lv) in [32].
[ 4 9〕 指標遺伝子または指標遺伝子と機能的に同等な遺伝子の皮膚における 発現強度を上昇させたトランスジヱニック非ヒト脊椎動物からなる乾癬モデル 動物であって、 指標遺伝子が [ 3 2〕 における i)群おょぴ iii)群に記載の群か ら選択されたいずれかの遺伝子であるモデル動物。  [49] A psoriatic model animal comprising a transgenic non-human vertebrate with an increased expression level in the skin of an indicator gene or a gene functionally equivalent to the indicator gene, wherein the indicator gene is as defined in [32]. i) a model animal which is any gene selected from the group described in group iii) group.
〔5 0〕 非ヒト脊椎動物がマウスである 〔4 9〕 に記載のモデル動物。  [50] the model animal of [49], wherein the non-human vertebrate is a mouse;
〔5 1〕 指標遺伝子または指標遺伝子と機能的に同等な遺伝子の皮膚における 発現強度を低下させたトランスジエニック非ヒト脊椎動物からなる乾癬モデル 動物であって、 指標遺伝子が 〔3 2〕 における ii)群おょぴ iv)群から選択され たいずれかの遺伝子であるモデル動物。
Figure imgf000045_0001
[51] A psoriatic model animal comprising a transgenic non-human vertebrate with reduced expression intensity in the skin of an indicator gene or a gene functionally equivalent to the indicator gene, wherein the indicator gene is defined as ii in [32]. ) Group iv) a model animal which is any gene selected from the group.
Figure imgf000045_0001
〔5 2〕 非ヒト脊椎動物がマウスである 〔5 1〕 に記載のモデル動物。  [52] The model animal according to [51], wherein the non-human vertebrate is a mouse.
〔5 3〕 次の工程を含む、 乾癬の治療薬のスクリーニング方法であって、 指標 遺伝子が 〔3 2〕 における i)〜： Lv)のいずれかに記載の群から選択されたいずれ かの遺伝子、 または指標遺伝子と機能的に同等な遺伝子であるスクリーニング 方法。  [53] A method for screening a therapeutic agent for psoriasis, comprising the following steps, wherein the indicator gene is any one selected from the group described in any one of i) to Lv) in [32]. Or a screening method that is a gene functionally equivalent to the indicator gene.
( 1 ) 指標遺伝子の転写調節領域と、 この転写調節領域の制御下に発現するレ ポーター遺伝子とを含むベクターを導入した細胞と候補化合物を接触させ る工程、  (1) contacting a candidate compound with a cell into which a vector containing a transcription regulatory region of an indicator gene and a reporter gene expressed under the control of the transcription regulatory region has been introduced;
( 2 ) 前記レポーター遺伝子の活性を測定する工程、 および  (2) measuring the activity of the reporter gene, and
( 3 ) 候補ィヒ合物を接触させない対照と比較して、 i)群または iii)群の指標 遺伝子については前記レポーター遺伝子の発現レベルを低下させる化合物 を、 また ii)群または iv)群の指標遺伝子については前記レポーター遺伝子 の発現レベルを上昇させる化合物を選択する工程、  (3) a compound which decreases the expression level of the reporter gene for the indicator gene of group i) or group iii), and a group ii) or group iv), Selecting a compound that increases the expression level of the reporter gene for the indicator gene;
〔5 4〕 次の工程を含む、 乾癬の治療薬のスクリーニング方法であって、 指標 遺伝子が 〔3 2〕 における i)〜iv)のいずれかに記載の群から選択されたいずれ かの遺伝子、 または指標遺伝子と機能的に同等な遺伝子であるスクリーニング 方法。  (54) A method for screening a therapeutic agent for psoriasis, comprising the following steps, wherein the indicator gene is any one of the genes selected from the group according to any of i) to iv) in (32), Or a screening method in which the gene is functionally equivalent to the indicator gene.
( 1 ) 指標遺伝子によってコードされる蛋白質と候補化合物を接触させる工程、 (1) contacting a protein encoded by the indicator gene with a candidate compound,
( 2 ) 前記蛋白質の活性を測定する工程、 および (2) measuring the activity of the protein, and
( 3 ) 候補ィ匕合物を接触させない対照と比較して、 i)群または iii)群の指標 遺伝子については前記活性を低下させる化合物を、 また ii)群または iv)群 の指標遺伝子については前記活性を上昇させる化合物を選択する工程 (3) Compared to a control not contacted with the candidate conjugate, the indicator gene of the group i) or iii) is a compound that reduces the activity, and the indicator gene of the group ii) or iv) is Selecting a compound that increases the activity
〔5 5〕 〔4 5〕、 〔5 3〕、 および 〔5 4〕 のいずれかに記載のスクリーニング 方法によって得ることができる化合物を有効成分として含有する、 乾癬の治療 桌。 [55] A treatment for psoriasis, comprising as an active ingredient a compound obtainable by the screening method according to any one of [45], [53], and [54].
〔5 6〕 指標遺伝子、 またはその一部のアンチセンス DNAを有効成分として含 4 5:—一一一- J [56] An indicator gene or a part thereof antisense DNA is contained as an active ingredient. 4 5: —111-J
む乾癬の治療薬であって、 指標遺伝子が 〔3 2〕 における i)または iii)のいず れかに記載の群から選択されたいずれかの遺伝子である治療薬。 A therapeutic agent for psoriasis, wherein the indicator gene is any gene selected from the group according to any one of i) and iii) in [32].
〔5 7〕 指標遺伝子によってコードされる蛋白質のアミノ酸配列を含むぺプチ ドを認識する抗体を有効成分として含む、 乾癬の治療薬であって、 指標遺伝子 が 〔3 2〕 における i)または iii)のいずれかに記載の群から選択されたいずれ かの遺伝子である治療薬。  (57) a therapeutic agent for psoriasis, comprising as an active ingredient an antibody that recognizes a peptide containing the amino acid sequence of the protein encoded by the indicator gene, wherein the indicator gene is (i) or (iii) in (32)) A therapeutic agent which is any gene selected from the group described in any of the above.
〔5 8〕 指標遺伝子、 または指標遺伝子によってコードされる蛋白質を有効成 分として含む、 乾癬の治療薬であって、 指標遺伝子が 〔3 2〕 における ii)また は iv)に記載の群から選択されたいずれかの遺伝子である治療薬。  [58] A therapeutic agent for psoriasis, comprising an indicator gene or a protein encoded by the indicator gene as an active ingredient, wherein the indicator gene is selected from the group described in ii) or iv) in [32] Therapeutic agents that are any of the genes that were performed.
〔5 9〕 指標遺伝子を測定するためのプローブを固定した乾癬の診断用 DNAチ ップであって、 指標遺伝子が 〔3 2〕 に記載された i)〜： ίν)群のいずれかから選 択された少なくとも 1種類の遺伝子である DNAチップ。  [59] A DNA chip for psoriasis diagnosis on which a probe for measuring an indicator gene is immobilized, wherein the indicator gene is selected from any of the i) to: ： ν) groups described in [32]. A DNA chip that is at least one selected gene.
あるいは本発明は、 〔4 5〕、 〔5 3〕、 および 〔5 4〕 のいずれかに記載のス タリ ^ユング方法によって得ることができる化合物を投与する工程を含む、 乾 癬の治療方法に関する。 また本発明は、 〔4 5〕、 〔5 3〕、 および 〔5 4〕 のい ずれかに記載のスクリ一ユング方法によって得ることができる化合物の、 乾癬 の治療用医薬組成物の製造における使用に関する。  Alternatively, the present invention relates to a method for treating psoriasis, which comprises a step of administering a compound obtainable by the method according to any one of [45], [53], and [54]. . The present invention also provides a use of a compound obtainable by the screening method of any one of (45), (53) and (54) in the manufacture of a pharmaceutical composition for treating psoriasis. About.
加えて本発明は、 次の成分（1)または（2)を投与する工程を含む、 乾癬の治療 方法に関する。 あるいは本発明は、 次の成分（1)または（2)の、 乾癬の治療用医 薬組成物の製造における使 に関する。  In addition, the present invention relates to a method for treating psoriasis, comprising a step of administering the following component (1) or (2). Alternatively, the present invention relates to the use of the following component (1) or (2) in the manufacture of a pharmaceutical composition for treating psoriasis.
(1)上記 i)または iii)に記載の遺伝子、 またはその一部のアンチセンス DNA、 (1) the gene according to i) or iii) above, or a part thereof antisense DNA,
(2)上記 i)または i i i)に記載の遺伝子によってコードされる蛋白質を認識す る抗体 (2) an antibody that recognizes a protein encoded by the gene described in i) or iii) above
更に本突明は、 次の成分 (3)または (4)を投与する工程を含む、 乾癬の治療方 法に関する。 あるいは本発明は、 次の成分 (3)または (4)の、 乾癬の治療用医薬 組成物の製造における使用に関する。
Figure imgf000047_0001
The present invention further relates to a method for treating psoriasis, comprising the step of administering the following component (3) or (4): Alternatively, the present invention relates to the use of the following component (3) or (4) in the manufacture of a pharmaceutical composition for treating psoriasis.
Figure imgf000047_0001
(3)上記 ii)または iv)に記載の遺伝子、  (3) the gene according to ii) or iv) above,
(4)上記 i i)または i V)に記載の遺伝子によってコードされる蛋白質  (4) a protein encoded by the gene described in ii) or i V) above
本発明において、 アレルギー性疾患（allergic disease)とはアレルギー反応 の関与する疾患の総称である。 より具体的には、 アレルゲンが同定され、 ァレ ルゲンへの曝露と病変の発症に深い結びつきが証明され、 その病変に免疫学的 な機序が証明されることと定義することができる。 ここで、 免疫学的な機序と は、 ァレルゲンの刺激によって白血球細胞が免疫応答を示すことを意味する。 ァレルゲンとしては、 ダニ抗原や花粉抗原等を例示することができる。  In the present invention, an allergic disease is a general term for diseases associated with allergic reactions. More specifically, it can be defined as identifying an allergen, demonstrating a deep link between exposure to the allergen and the development of the lesion, and demonstrating an immunological mechanism for the lesion. Here, the immunological mechanism means that leukocyte cells show an immune response by allergen stimulation. Examples of allergens include mite antigens and pollen antigens.
代表的なアレルギー性疾患には、 アトピー性皮膚炎、 気管支喘息、 アレルギ 一性鼻炎、 花粉症、 あるいは昆虫アレルギー等を示すことができる。 アレルギ 一素因（allergic diathesis)とは、 アレルギー性疾患を持つ親から子に伝えら れる遺伝的な因子である。 家族性に発症するアレルギー性疾患はアトピー性疾 患とも呼ばれ、 その原因となる遺伝的に伝えられる因子がアトピー素因である。 ァトピー性皮膚炎は、 ァトピー性疾患のうち、 特に皮膚炎症状を伴う疾患に対 して与えられた総称である。  Representative allergic diseases can include atopic dermatitis, bronchial asthma, allergic rhinitis, hay fever, or insect allergy. Allergic diathesis is a genetic factor transmitted from parents to children with an allergic disease. A familial allergic disease is also called an atopic disease, and the genetic factors that cause it are predisposed to atopy. Atopic dermatitis is a generic term given to atopic diseases, particularly those associated with skin inflammatory conditions.
本発明において、 アトピー性皮膚炎の指標とすることができる遺伝子を、 AD 指標遺伝子という。 また AD指標遺伝子がコードするアミノ酸配列からなる蛋白 質を AD指標蛋白質という。 AD指標遺伝子は特に断らない限り、 a)- d)、 c' )およ び d' )、 ならびに A) - D)に記載された遺伝子から選択されたいずれか 1つまたは 複数の任意の遺伝子を示す用語として用いられる。  In the present invention, a gene that can be used as an indicator of atopic dermatitis is referred to as an AD indicator gene. A protein consisting of the amino acid sequence encoded by the AD indicator gene is called an AD indicator protein. Unless otherwise specified, the AD indicator gene is any one or more genes selected from the genes described in a) -d), c ') and d'), and A) -D) Is used as a term for
本発明の AD指標遺伝子において、 次に示す遺伝子群から選択された遺伝子は、 前記 a)群または b)群の遺伝子として好ましい。 これらの遺伝子は、 アトピー性 皮膚炎患者の皮疹部における発現レベルがァトピー性皮膚炎患者の無疹部に比 ベて高い一 a)群一、 または低い一 b)群一 AD指標遺伝子群に含まれ、 かつ乾癬患 者の皮疹部と無疹部の比較においては発現レベルに有意な差が見られなかった 遺伝子である。 これらの AD指標遺伝子は、 アトピー性皮膚炎患者において特異 的に発現レベルが変化している遺伝子である。 In the AD indicator gene of the present invention, a gene selected from the following gene group is preferable as the gene of the group a) or b). These genes are included in the AD index gene group with a higher expression level in the rash area of atopic dermatitis patients than in the rash area of atopic dermatitis patients. It is a gene for which there was no significant difference in expression level between the rash and pustular areas of psoriatic patients. These AD indicator genes are unique in patients with atopic dermatitis It is a gene whose expression level is changed.
a)群の遺伝子として好ましい遺伝子： metalloproteinase (HME)、 type IV coll agenaseN cathepsin Z precursor (CT^L) s disintegrin- protease、 pro-cathep sin L (major excreted protein MEP)、 skin collagenases SPUVE (protease, serine, 23)、 Proprotein convertase subti丄 isin/kexin typel、 tissue inhib itor of metalloproteinases beta-migrating plasminogen activator inhibi tor I、 IL— 13Ral、 IFN-beta 2a (IL— 6)、 heparin— binding EGF-like growth fa ctor、 GM-CSFR beta, interleukin 8 (IL8)、 MCP-1、 EBIl- ligand chemokine、 SLC、 GRO - beta、 monocyte chemotactic protein— 2、 CCR1、 lymph node homing receptor I L- selectin、 endothelial leukocyte adhesion molecule 1 (ELAM - 1)、 leukocyte adhesion protein (LFA- 1/Mac - l/pl50， 95 family) beta、 TNFAI P6 (tumor necrosis factor, alpha-induced protein 6)、 M130 antigen extra cellular variant / CD163、 CD53 glycoprotein^ T200 leukocyte common anti gen (CD45， LC— A) isoform卜 3、 THY— 1 (CD90)、 leucocyte immunoglobulin-li ke receptor- 3 ( R- 3)、 tenascin- C、 a丄 pha— 1 type XV collagen^ cartilage oligomeric matrix protein (COMP)ヽ proteoglycan 1、 immunoglobulin lambda light chain、 Fc—epsilon -; receptor gamma - chain、 IgG low affinity Fc frag merit receptor (CD32)、 immunoglobulin heavy constant gamma 3 (G3m marke r)、 immunoglobulin kappa constant^ hemopoietic cell protein- tyrosine ki nase (HCK)、 KIAA0687 / MAP4K4, ornithine decarboxylase ODC (EC 4. 1. 1. 1 7)、 phospholipase A2， group IIA (platelets, synovial fluid)、 nicotinami de N-methyltransf erase (NNMT)、 actin related protein 2/3 complex, subun it IB (41 kD)、 myosin IB、 gamma- interferon - induci o丄 e protein (IP - 30)、 R AB31、 regulator of G- protein signall ing 1 (BL34)、 TNRC3、 insulin-like gr owth factor binding protein 4 (IGFBP4)、 ne丄— related protein 2、 neuronal tissue— enriched acidic protein (NAP - 22)、 DKFZp58600118 / KIAA1199, lys 4 8に二—— a) Genes preferred as group genes: metalloproteinase (HME), type IV collagenase N cathepsin Z precursor (CT ^ L) s disintegrin-protease, pro-cathepsin L (major excreted protein MEP), skin collagenase s SPUVE (protease) , serine, 23), Proprotein convertase subti 丄 isin / kexin typel, tissue inhibitor of metalloproteinases beta-migrating plasminogen activator inhibi tor I, IL-13Ral, IFN-beta 2a (IL-6), heparin-binding EGF-like growth Factor, GM-CSFR beta, interleukin 8 (IL8), MCP-1, EBIl-ligand chemokine, SLC, GRO-beta, monocyte chemotactic protein-2, CCR1, lymph node homing receptor I L-selectin, endothelial leukocyte adhesion molecule 1 (ELAM-1), leukocyte adhesion protein (LFA-1 / Mac-l / pl50, 95 family) beta, TNFAI P6 (tumor necrosis factor, alpha-induced protein 6), M130 antigen extra cellular variant / CD163, CD53 glycoprotein ^ T200 leukocyte common antigen (CD45, LC-A) isoform 3, THY-1 (CD9 0), leucocyte immunoglobulin-li ke receptor-3 (R-3), tenascin-C, a 丄 pha— 1 type XV collagen ^ cartilage oligomeric matrix protein (COMP) ヽ proteoglycan 1, immunoglobulin lambda light chain, Fc—epsilon- ; receptor gamma-chain, IgG low affinity Fc frag merit receptor (CD32), immunoglobulin heavy constant gamma 3 (G3m marker), immunoglobulin kappa constant ^ hemopoietic cell protein- tyrosine kinase (HCK), KIAA0687 / MAP4K4, ornithine decarboxylase ODC (EC 4.1.1.17), phospholipase A2, group IIA (platelets, synovial fluid), nicotinami de N-methyltransf erase (NNMT), actin related protein 2/3 complex, subun it IB (41 kD), myosin IB, gamma-interferon-induci o 丄 e protein (IP-30), R AB31, regulator of G-protein signalling 1 (BL34), TNRC3, insulin-like growth factor binding protein 4 (IGFBP4), ne 丄— Related protein 2, neuronal tissue— enriched acidic protein (NAP-22), DKFZp58600118 / KIAA1199, lys 4 8 to 2
osomal— associated mult i transmembrane protein (LAPTn )ノ、 KIM0296、 serum amyloid Al、 TYRO protein tyrosine kinase binding protein^ fatty acid bi nding protein homologue (PA - F層)、 fibrinogen - like 2、 およぴ six transme mbrane epithelial antigen of the prostate (STEAP) osomal--associated mult i transmembrane protein (LAPTn), KIM0296, serum amyloid Al, TYRO protein tyrosine kinase binding protein ^ fatty acid binding protein homologue (PA-F layer), fibrinogen-like 2, and six transme mbrane epithelial antigen of the prostate (STEAP)
b)群の遺伝子として好ましい遺伝子： cathepsin V、 SERPINB7 (serine (or cys teme) proteinase inhibitor, clade B (ovalbuminノ， member 7,、 cytokerati n 15、 desmin、 extracellular matrix protein 2、 KIAA0537N deoxyribonuclea se I - like 2 (DNAS1L2) N phosphoenolpyruvate carboxykinase (PCK1)、 3- hydr oxy-3-methylglutaryl coenzyme A synthase arylacetamide deacetylaseN AT Pase, Cu++ transporting, alpha polypeptide (ATP7A)、 tyrosinase (TYR) N m onoamine oxidase A、 Aldehyde dehydrogenase 5 family, member Al、 alcohol dehydrogenase 1A (class I) , alpha polypeptide^ alcohol dehydrogenase 1 C (class I) , gamma polypeptide^ degenerative spermatocyte homolog (sphi ngoli id delta 4 desaturase) s alpha- 2- glycoprotein 1， zinc、 perilipin、 lipoprotein lipase^ b) Genes preferred as group genes: cathepsin V, SERPINB7 (serine (or cys teme) proteinase inhibitor, clade B (ovalbumin, member 7, cytokeratin 15, desmin, extracellular matrix protein 2, KIAA0537 N deoxyribonuclea se I- like 2 (DNAS1L2) N phosphoenolpyruvate carboxykinase (PCK1), 3- hydr oxy-3-methylglutaryl coenzyme A synthase arylacetamide deacetylase N AT Pase, Cu ++ transporting, alpha polypeptide (ATP7A), tyrosinase (TYR) N m onoamine oxidase A, Aldehyde dehydrogenase 5 family, member Al, alcohol dehydrogenase 1A (class I), alpha polypeptide ^ alcohol dehydrogenase 1 C (class I), gamma polypeptide ^ degenerative spermatocyte homolog (sphi ngoli id delta 4 desaturase) s alpha- 2-glycoprotein 1, zinc, perilipin, lipoprotein lipase ^
aldehyde dehydrogenase 3 family, member A2、 Hemoglobin alpha 1， alpha 2 chain、 class I homeoprotein (H0XA9)、 promyelocytic leukemia zinc f inge T protein (PLZF) N calcium channel, voltage— dependent, alpha 1H subunits sodium channel, nonvoltage-gated 1， betaN LIGl (ortholog of mouse integ ral membrane glycoproteinし上 G- 1)、 WFSl ( oltram syndrome 1)、 progestero ne receptor membrane component 2、 peanut- like 1 (Drosophila) N type 1 an giotensin II receptor, variant 1—5、 EphB6、 betacellulin、 proline rich 4 (lacrimal)、 retinol binding protein 4、 DKFZP434G0310 (hypothetical pro tein) , loricrin, DKFZp586H2123 KIM0624、 DKFZp564D206、 および DKFZp586F 1223 aldehyde dehydrogenase 3 family, member A2, Hemoglobin alpha 1, alpha 2 chain, class I homeoprotein (H0XA9), promyelocytic leukemia zinc f inge T protein (PLZF) N calcium channel, voltage—dependent, alpha 1H subunit s sodium channel, nonvoltage- gated 1, beta N LIGl (ortholog of mouse integral membrane glycoprotein G-1), WFSl (oltram syndrome 1), progestero ne receptor membrane component 2, peanut- like 1 (Drosophila) N type 1 an giotensin II receptor, variant 1-5, EphB6, betacellulin, proline rich 4 (lacrimal), retinol binding protein 4, DKFZP434G0310 (hypothetical pro tein), loricrin, DKFZp586H2123 KIM0624, DKFZp564D206, and DKFZp586F 1223
—方、 本発明の AD指標遺伝子において、 次に示す遺伝子群から選択された遺 伝子は、 前記 c' )群または d' )群の遺伝子として好ましい。 これらの遺伝子は、 ァトピー性皮膚炎患者の無疹部における発現レベルが健常者に比べて高い一 c， ) 群一、 または低い一 d' )群一AD指標遺伝子群に含まれ、 かつ乾癬患者の無疹部と 健常者の比較においては発現レベルに有意な差が見られなかった遺伝子である。 これらの AD指標遺伝子も、 アトピー性皮膚炎患者において特異的に発現レベル が変化している遺伝子である。 On the other hand, in the AD indicator gene of the present invention, a gene selected from the following gene group: The gene is preferred as a gene belonging to the group c ′) or d ′). These genes are included in the AD index gene group in which the expression level in the eruption area of atopic dermatitis patients is higher than that in healthy subjects compared to healthy subjects. No significant difference was found in the expression level in the comparison between the rash-free area and healthy subjects. These AD indicator genes are also genes whose expression levels are specifically changed in patients with atopic dermatitis.
c ノ の遺 1 子として好ましレヽ ¾E?feナ： BTF3 protein homologue、 general tran scription factor I IF, polypeptide 2, 30kDa、 alternative activated macro phage specific CC chemokine 1、 complement component 1, q subcomponent, beta polypeptide^ transforming growth factor, beta receptor III (betagl yean, 300kD)、 branched chain alpha-ketoacid dehydrogenase kinaseN ATPas e, Ca++ transporting, ubiquitous^ tyrosinase - related protein 1、 histidi ne ammonia -丄 yase、 androgen— regulated short-chain dehydrogenase/ reductas e 1、 gap junction protein, beta 3, 31kD (connexin 31)、 KI 0440、 lympho id-restricted membrane protein (LRMP)、 matrilysin (MMP7)、 specific gran ule protein (28 kDa) (SGP28)、 type I sigma receptor % FK506 binding prot ein IB, 12. 6 kDa、 Prolactin - Induced Protein, SET binding factor 1 (SBF 1)、 および FLJ12525 ? E fena: BTF3 protein homologue, general transcription factor I IF, polypeptide 2, 30kDa, alternative activated macro phage specific CC chemokine 1, complement component 1, q subcomponent, beta polypeptide ^ transforming growth factor, beta receptor III (betagl yean, 300kD), branched chain alpha-ketoacid dehydrogenase kinase N ATPase, Ca ++ transporting, ubiquitous ^ tyrosinase-related protein 1, histidi ne ammonia-丄 yase, androgen— regulated short-chain dehydrogenase / reductas e 1, gap junction protein, beta 3, 31kD (connexin 31), KI 0440, lympho id-restricted membrane protein (LRMP), matrilysin (MMP7), specific gran ule protein (28 kDa) (SGP28), type I sigma receptor % FK506 binding protein IB, 12.6 kDa, Prolactin-Induced Protein, SET binding factor 1 (SBF 1), and FLJ12525
d' )群の遺伝子として好ましい遺伝子： Idl、 BTG2、 zinc finger protein 36, C 3H type-like 1、 EGR1 (early growth response 1)、 MIP - 1 - alpha、 MCP1、 tumo r necrosis factor receptor superfamily, member 13B、 HB15 / CD83、 CD95, F AS、 CD69、 T cell receptor delta locus、 caspase 3, apoptosis— related cys teine protease^ serine (or cysteine) proteinase inhibitor, clade I (neu roserpin) , member 1、 SERPINE1S prostaglandin D2 synthase 21 kDa (brain) cholesterol 25- hydroxylaseヽ glutathione S - transferase M3 (brain) N prote in phosphatase 5, catalytic subunit、 phosphodiesterase 3B、 regulator of G- protein signalling 16、 heparin- binding EGF - like growth f actor pleio trophin、 weel tyrosine kinase^ SMARCD3、 IgG Fc binding protein^ chorion ic gonadotropin beta subunit、 keratin, hair, acidic, 3A、 37 kDa leucin e - rich repeat (LRR) protein、 brain abundant, membrane attached signal p rotein 1、 SEC24 related gene family, member D (S. cerevisiae)、 Friedrei ch ataxias zinc finger protein 187、 zinc finger protein 337、 MLLT10、 co llagen, type XIV, alpha 1 (undulin)、 molybdenum cofactor synthesis 3、 g uanylate binding protein 1, interferon-inducible, 67kDa、 ras homo log gen e family, member E、 armadillo repeat protein ALEX2、 keratin, hair, acid ic, 1、 YDD19 protein,, chromosome condensation 1、 dermatopontin P311 r otein、 syntaxin 11、 NDRG family member 4、 rearranged L-myc fusion seque nce、 clone 24790、 KIAA1095 protein、 FLJ12280, ESTs (Accession No. AC0049 40)、 および ESTs (Accession No. AI829701) d ') Preferred genes as group genes: Idl, BTG2, zinc finger protein 36, C3H type-like 1, EGR1 (early growth response 1), MIP-1-alpha, MCP1, tumor rcrocrosis factor receptor superfamily, member 13B, HB15 / CD83, CD95, FAS, CD69, T cell receptor delta locus, caspase 3, apoptosis—related cys teine protease ^ serine (or cysteine) proteinase inhibitor, clade I (neu roserpin), member 1, SERPINE1 S prostaglandin D2 synthase 21 kDa (brain) cholesterol 25-hydroxylase ヽ glutathione S-transferase M3 (brain) N prote in phosphatase 5, catalytic subunit, phosphodiesterase 3B, regulator of G-protein signaling 16, heparin-binding EGF-like growth f actor pleio trophin, weel tyrosine kinase ^ SMARCD3, IgG Fc binding protein ^ chorion ic gonadotropin beta subunit, keratin, hair, acidic, 3A, 37 kDa leucin e-rich repeat (LRR) protein, brain abundant, membrane attached signal protein 1, SEC24 related gene family, member D (S. cerevisiae), Friedrei ch ataxia s zinc finger protein 187, zinc finger protein 337, MLLT10, collagen, type XIV, alpha 1 (undulin), molybdenum cofactor synthesis 3, guanylate binding protein 1, interferon-inducible, 67kDa, ras homolog gene family, member E, armadillo repeat protein ALEX2, keratin, hair, acid ic, 1, YDD19 protein, , chromosome condensation 1, dermatopontin P311 r otein, syntaxin 11, NDRG family member 4, rearranged L-myc fusion sequence, clone 24790, KIAA1095 protein, FLJ12280, ESTs (Accession No.AC0049 40), and ESTs (Accession No.AI829701) )
また本発明において、 乾癬の指標とすることができる遺伝子を、 乾癬指標遺 伝子という。 また乾癬指標遺伝子がコードするァミノ酸配列からなる蛋白質を 乾癬指標蛋白質という。 乾癬指標遺伝子は特に断らない限り、 i) - iv)に記載さ れた遺伝子から選択されたいずれか 1つまたは複数の任意の遺伝子を示す用語 として用いられる。 更に、 以降、 特に疾患を特定せず、 単に指標遺伝子または 指標蛋白質と記載するときは、 前記 AD指標遺伝子 （および AD指標蛋白質） と 前記乾癬指標遺伝子 （乾癬指標蛋白質） の両方を含む用語として用いる。  In the present invention, a gene that can be used as an indicator of psoriasis is referred to as a psoriasis indicator gene. A protein consisting of an amino acid sequence encoded by a psoriasis indicator gene is called a psoriasis indicator protein. Unless otherwise specified, the psoriasis indicator gene is used as a term indicating any one or more arbitrary genes selected from the genes described in i) to iv). Further, hereinafter, when a disease is not particularly specified and is simply referred to as an indicator gene or an indicator protein, it is used as a term including both the AD indicator gene (and the AD indicator protein) and the psoriasis indicator gene (psoriasis indicator protein). .
本発明の乾癬指標遺伝子において、 次に示す遺伝子群から選択された遺伝子 は、 前記 i)群または ii)群の遺伝子として好ましい。 これらの遺伝子は、 乾癬 患者の皮疹部における発現レベルが乾癬患者の無疹部に比べて高い一 i)群一、 または低い一 ii)群一乾癬指標遺伝子群に含まれ、 かつアトピー性皮膚炎患者の 皮瘆部と無疹部の比較においては発現レベルに有意な差が見られなかった遺伝 子である。 これらの乾癬指標遺伝子は、 乾癬患者において特異的に発現レベル が変化している遺伝子である。 Among the psoriasis indicator genes of the present invention, genes selected from the following gene groups are preferable as the genes of the above-mentioned group i) or group ii). These genes are included in the psoriatic index gene group, i. This gene did not show a significant difference in the expression level between the skin area and the eruption area of the patient. These psoriatic index genes are specifically expressed in psoriatic patients Is the gene that is changing.
i〉群の遺 ナとして好ましい遺伝子： cellular retinoic acid binding protei n 2、 proteasome (prosome, macropain) activator subunit 2、 interferon in duced 6-16 proteinN heat shock 70kDa protein 4、 flap structure-specific endonuclease 1、 NME1、 eye 1 in-dependent kinase inhibitor 3、 ubiquitin— c onjugating enzyme E2C、 calreticulin^ CDC2 gene、 RAN、 liver arginase (AR Gl)ヽ connexin 43 (GJAl, Cx43)ヽ interleukin 1 receptor antagonist^ ATP-b inding cassette, sub-family A (ABCl) , member 12、 M- phase phosphoproteini> Preferred genes for the group: cellular retinoic acid binding protein 2, proteasome (prosome, macropain) activator subunit 2, interferon in duced 6-16 protein N heat shock 70kDa protein 4, flap structure-specific endonuclease 1, NME1 , Eye 1 in-dependent kinase inhibitor 3, ubiquitin-conjugating enzyme E2C, calreticulin ^ CDC2 gene, RAN, liver arginase (AR Gl) ヽ connexin 43 (GJAl, Cx43) ヽ interleukin 1 receptor antagonist ^ ATP-b inding cassette, sub-family A (ABCl), member 12, M-phase phosphoprotein
6、 creatine kinase, mitochondrial 1、 Nedd4 binding protein 1、 solute c arrier family 7， member 5、 acid phosphatase, prostate^ plakophilin 1、 U DP glycosyl transferase 1 family, polypeptide A4、 ATPase, H+/ + transpor ting, nongastric, alpha polypeptide^ cytoskeleton - associated protein 4、 glucosidase, beta; acid、 interferon-inducible 56 Kd proteinN low densit lipoprotein receptor Λ transglutaminase 3、 arachidonate 12-lipoxygenas e， 12R type、 CYP7B1、 tripartite motif-containing 14、 hypothetical prote in FLJ21168、 heme oxygenase (decycling) 1、 S100 calcium binding protein6, creatine kinase, mitochondrial 1, Nedd4 binding protein 1, solute carrier family 7, member 5, acid phosphatase, prostate ^ plakophilin 1, UDP glycosyl transferase 1 family, polypeptide A4, ATPase, H + / + transpor ting, nongastric, alpha polypeptide ^ cytoskeleton-associated protein 4, glucosidase, beta; acid, interferon-inducible 56 Kd protein N low densit lipoprotein receptor Λ transglutaminase 3, arachidonate 12-lipoxygenas e, 12R type, CYP7B1, tripartite motif-containing 14, hypothetical prote in FLJ21168, heme oxygenase (decycling) 1, S100 calcium binding protein
P、 gene from PAC 747L4N SAM domain and HD domain 1、 arylsulfatase F、 p otassium inwardly-rectifying channel, subfamily J, member 15、 BUBl budd ing uninnibited by benz imidazoles 1 homolog beta (yeast) N SPllO nuclear body protein isoform b、 guanylate binding protein 1 (GBP1)、 GM2 gangli oside activator proteins complement factor B preproproteinN squalene ep oxidase^ solute carrier family 5 (sodium/glucose cotransporter) , memberP, gene from PAC 747L4 N SAM domain and HD domain 1, arylsulfatase F, potassium inwardly-rectifying channel, subfamily J, member 15, BUBl budding uninnibited by benz imidazoles 1 homolog beta (yeast) N SPllO nuclear body protein isoform b , Guanylate binding protein 1 (GBP1), GM2 gangli oside activator protein s complement factor B preproprotein N squalene ep oxidase ^ solute carrier family 5 (sodium / glucose cotransporter), member
1、 ZW10 interactor ZwintN kallikrein 13、 interferon regulatory factor N-myc (and STAT) interactorゝ Stat2 "tripartite motif-containing 22、 kinesin - like 6、 kallikrein 10、 ribonucleotide reductase M2 polypeptide、 chromosome 1 open reading frame 29ヽ Sjogren syndrome antigen Alヽ gamma— glutamyl hydrolaseN lymphocyte antigen 6 complex, locus E interleukin - 1 receptor antagonistN interferon - induced protein 44 lectin, galactosi de-binding, soluble, 3 binding protein^ retinoblastoma binding protein 6 vipirin interferon - induced protein with t e tratr i copept i de repeats 4 S100 calcium binding protein A12 (calgranulin C)、 bone marrow stromal c ell antigen 2 chromosome 20 open reading frame 1 aquaporin 3 cystati n A (stefin A)、 KIAA0186 retinoDlastoma- associated protein HEC NSl-as sociated protein 1 topoisomerase (DNA) II alpha 170kDa H2A histone fa mily, member X chemokine exodus— 1 pituitary tumor— transforming 1 SCO cytochrome oxidase deficient homolog 2 (yeast) CDC28 protein kinase r egulatory subunit 2 kinesin-like 1 histidine a onia— lyase hypotheti cal protein FLJ10534 cyclin El chromosome 1 open reading frame 34 ce llular retinoic acid binding protein 2 TTK protein kinase^ acid phosph atase, prostate^ interleukin 8 receptor beta (IL8RB) N RAB27A MX2S thym idine kinase 1 interferon-inducible ¾o Kd protein^ serum/glucocorticoi d regulated kinase^ EphA2N nitric oxide synthase 2A plasminogen activa tor, tissue type GM2 ganglioside activator proteinN KIAA0963 protein^ kallikrein 13 ATPase, Class V type 10B、 およぴ GART 1, ZW10 interactor Zwint N kallikrein 13, interferon regulatory factor N-myc (and STAT) interactor ゝ Stat2 `` tripartite motif-containing 22, kinesin-like 6, kallikrein 10, ribonucleotide reductase M2 polypeptide, chromosome 1 open reading frame 29 ヽ Sjogren syndrome antigen Al ヽ gamma— glutamyl hydrolase N lymphocyte antigen 6 complex, locus E interleukin-1 receptor antagonist N interferon-induced protein 44 lectin, galactosi de-binding, soluble, 3 binding protein ^ retinoblastoma binding protein 6 vipirin interferon-induced protein with te tratr i copept i de repeats 4 S100 calcium binding protein A12 (calgranulin C), bone marrow stromal cell antigen 2 chromosome 20 open reading frame 1 aquaporin 3 cystatin A (stefin A), KIAA0186 retinoDlastoma- associated protein HEC NSl-as sociated protein 1 topoisomerase (DNA ) II alpha 170kDa H2A histone fa mily, member X chemokine exodus— 1 pituitary tumor— transforming 1 SCO cytochrome oxidase deficient homolog 2 (yeast) CDC28 protein kinase r egulatory subunit 2 kinesin-like 1 histidine a onia— lyase hypotheti cal protein FLJ10534 cyclin El chromosome 1 open reading frame 34 ce llular retinoic acid binding protein 2 TTK protein kinase ^ acid phosphatase, prostate ^ interleukin 8 receptor beta (IL8RB) N RAB27A M X2 S thym idine kinase 1 interferon-inducible ¾o Kd protein ^ serum / glucocorticoid d regulated kinase ^ EphA2 N nitric oxide synthase 2A plasminogen activa tor, tissue type GM2 ganglioside activator protein N KIAA0963 protein ^ kallikrein 13 ATPase, Class V type 10B Yo GART
ii)群の遺伝子として好ましい遺伝子： actin, alpha 2, smooth muscle, aorta actin, gamma 2 smooth muscle, enteric^ cisplatin resistance associated^ growth arrest— specif ic 6 insulin-like growt factor binding protein 6 (IGFBP6)、 insulin induced protein 1 (INSIG1)、 PDGF receptor beta— like t umor suppressor (PRLTS)、 R— ras sarcospan (Kras oncogene- associated gen e)、 fibroblast growth factor (FGF) receptor - 1 f ibronectin 1 is of or in 1 preproprotein^ chromosome 21 open reading frame 25 seven in absentia h omolog 1 (Drosophila) x fatty acid desaturase 1 fatty acid desaturase 2 5 3:— 一 一- i ii) Genes preferred as group genes: actin, alpha 2, smooth muscle, aorta actin, gamma 2 smooth muscle, enteric ^ cisplatin resistance associated ^ growth arrest—specific 6 insulin-like growt factor binding protein 6 (IGFBP6), insulin induced protein 1 (INSIG1), PDGF receptor beta--like tumor suppressor (PRLTS), R--ras sarcospan (Kras oncogene-associated gene), fibroblast growth factor (FGF) receptor-1 f ibronectin 1 is of or in 1 preproprotein ^ chromosome 21 open reading frame 25 seven in absentia h omolog 1 (Drosophila) x fatty acid desaturase 1 fatty acid desaturase 2 5 3: — one one-i
Rho-related BTB domain containing 3、 matri in 2、 adipose specific 2、 LI M protein^ LIM domain binding 2 / CLIM1 myosin light chain kinase (MLC K)、 myosin, light polypeptide 9, regulatory^ tropomyosin 1 (alpha)、 cys teine-rich protein 1 (intestinal)、 reversion- inducing - cysteine- rich pro tein with kazal motifs、 amine oxidase, copper containing 3 (vascular ad hesion protein 1)、 cytochrome c oxidase subunit Vila polypeptide 1 (mus cle)、 chemokine (C - C motif) ligand 14、 ocular development-associated ge ne、 ephrin— B2、 Na, K-ATPase subunit alpha 2 (ATP1A2)、 ATPase, Ca++ trans porting, ubiquitous、 aquaporin 9、 pleiotrophin^ cadherin 19， type 2、 WN T inhibitory factor 1、 T1 inducible signaling pathway protein 2、 ll—b eta-hydroxysteroid dehydrogenase (HSD11)、 myelin basic protein (MBP)、 p ro - galanin、 dihydropyrimidinase-like 3、 glypican - 4 (GPC4)、 acetylseroto nin O-methyltransf erase-like^ synuclein, ga贿 a、 connective tissue growt h f actor breast cancer anti-estrogen resistance 3、 heat shock 70kDa pr otein 2、 ets variant gene 1、 cAMP— dependent protein kinase subunit RII - beta、 microtubu e - associated protein, RP/EB family, member 2、 ATP-bindi ng cassette, sub-family C (CFTR/MRP) , member 3、 transmembrane 4 super fa mily member 2、 AXL receptor tyrosine kinase^ phospholamban^ Fc fragment of IgG binding protein^ microsomal glutathione S - transferase 3、 DEPP (decidual protein induced by progesterone) Λ Arg/Abl - interacting proteinRho-related BTB domain containing 3, matri in 2, adipose specific 2, LI M protein ^ LIM domain binding 2 / CLIM1 myosin light chain kinase (MLC K), myosin, light polypeptide 9, regulatory ^ tropomyosin 1 (alpha), cys teine-rich protein 1 (intestinal), reversion- inducing-cysteine-rich pro tein with kazal motifs, amine oxidase, copper containing 3 (vascular ad hesion protein 1), cytochrome c oxidase subunit Vila polypeptide 1 (mus cle), chemokine ( C-C motif) ligand 14, ocular development-associated gene, ephrin—B2, Na, K-ATPase subunit alpha 2 (ATP1A2), ATPase, Ca ++ trans porting, ubiquitous, aquaporin 9, pleiotrophin ^ cadherin 19, type 2, WN T inhibitory factor 1, T1 inducible signaling pathway protein 2, ll-beta-hydroxysteroid dehydrogenase (HSD11), myelin basic protein (MBP), pro-galanin, dihydropyrimidinase-like 3, glypican-4 (GPC4), acetylseroto nin O-methyltransf erase-like ^ synuclein, ga 贿 a, connective tissue grow t hf actor breast cancer anti-estrogen resistance 3, heat shock 70kDa protein 2, ets variant gene 1, cAMP—dependent protein kinase subunit RII-beta, microtubue-associated protein, RP / EB family, member 2, ATP-bindi ng cassette, sub-family C (CFTR / MRP), member 3, transmembrane 4 super fa mily member 2, AXL receptor tyrosine kinase ^ phospholamban ^ Fc fragment of IgG binding protein ^ microsomal glutathione S-transferase 3, DEPP (decidual protein induced by progesterone) Λ Arg / Abl-interacting protein
ArgBP2a (ArgBP2a)、 H0X2H mRNA from the Hox2 locus, frizzled— related pr otein、 G protein-coupled receptor, family C, group 5, member B、 GABA - A receptor pi subunit N mesenchyme homeo box 2 (growth arrest-specific hom eo box) keratin 7、 tumor-associated calcium signal transducer 1、 dioxi n - induci le cytochrome P450 (CYP1B1 interleukin 1 receptor, type II、 platelet/endothelial cell adhesion molecule (CD31 antigen) s GRB2— associa ted binding protein 2、 mitogen inducible 2、 transgelins deleted in live r cancer 1、 8-oxoguanine DNA glycosylase、 enolase 2, (gamma, neuronal) pinin, desmosome associated protein^ KIAA0367 gene、 KIAA0280 gene、 KIM 1053 protein^ KIAA0729 protein^ KIAA1467 protein, KIAA0716 protein, hyp othetical gene CG018、 hypothetical protein FLJ13612、 FLJ90798、 DKFZp586 11823、 およぴ DKFZp5640222 ArgBP2a (ArgBP2a), H0X2H mRNA from the Hox2 locus, frizzled-- related pr otein, G protein-coupled receptor, family C, group 5, member B, GABA-A receptor pi subunit N mesenchyme homeo box 2 (growth arrest-specific hom eo box) keratin 7, tumor-associated calcium signal transducer 1, dioxi n-induci le cytochrome P450 (CYP1B1 interleukin 1 receptor, type II, platelet / endothelial cell adhesion molecule (CD31 antigen) s GRB2— associa ted binding protein 2, mitogen inducible 2, transgelin s deleted in live r cancer 1, 8-oxoguanine DNA glycosylase, enolase 2, (gamma, neuronal) pinin, desmosome associated protein ^ KIAA0367 gene, KIAA0280 gene, KIM 1053 protein ^ KIAA0729 protein ^ KIAA1467 protein, KIAA0716 protein, hypothetical gene CG018, hypothetical protein FLJ13612, FLJ90798, DKFZp586 11823, and DKFZp5640222
—方、 本発明の乾癬指標遺伝子において、 次に示す遺伝子群から選択された 遺伝子は、 前記 iii)群または iv)群の遺伝子として好ましい。 これらの遺伝子 は、 乾癬患者の無疹部における発現レベルが健常者に比べて高い一 iii)群一、 . または低い— iv)群一乾癬指標遺伝子群に含まれ、 力つアトピー性皮膚炎患者の 無疹部と健常者の比較においては発現レベルに有意な差が見られなかった遺伝 子である。 これらの乾癬指標遺伝子も、 乾癬患者において特異的に発現レベル が変化している遺伝子である。  On the other hand, among the psoriasis indicator genes of the present invention, genes selected from the following gene groups are preferable as the genes of the group iii) or iv). These genes have a higher expression level in the eruption area of psoriasis patients than in healthy subjects. Iii) Group 1,. Or low. Iv) Group psoriasis index genes. The gene showed no significant difference in the expression level in the comparison between the rash-free area and healthy subjects. These psoriasis indicator genes are also genes whose expression levels are specifically changed in psoriatic patients.
iii)群の遺伝子として好ましい遺伝子： platelet factor 4 (PF4)、 actin, gam ma 2, smooth muscle, enteric、 interferon (alpha, beta and omega) recept or 2、 DNA topoisoraerase I、 CYP3A4、 eye 1 in-dependent kinase 2、 vascular endothelial growth factor -!)、 ABL1、 adducin 1 (alpha) isoform c、 KLRC3、 RAB2、 l-acylglycerol-3-phosphate 0-acyltransf erase 2、 tryptase, alpha^ homolog of Yeast RRP4、 MCM3、 hemoglobin, delta、 KI 1089、 zinc finger p rotein 44 (KOX 7)、 arylacetaiiiide deacetylase (esterase)、 synuclein, gam ma、 elastase 2, neutrophil, CYP3A5、 FCGR3A (CM6)、 likely ortholog of m ouse neuralin 1、 pyruvate carboxylase^ 2，， 5， -ol i goadeny 1 at e synthetase 1、 muscle RAS oncogene homology butyrophilin, subfamily 3, member A2、 c onnective tissue activation peptide III、 Arg/Abl - interacting protein Ar gBP2、 FLJ33034、 calpain 3、 bleomycin hydrolase, desmuslin、 TAF6L、 ESTs (Accession No. AW043812) , FLJ22269、 keratin 7、 scaffold attachment fact 5 5； 'ニニ： iii) Preferred genes as group genes: platelet factor 4 (PF4), actin, gamma 2, smooth muscle, enteric, interferon (alpha, beta and omega) recept or 2, DNA topoisoraerase I, CYP3A4, eye 1 in-dependent kinase 2, vascular endothelial growth factor-!), ABL1, adducin 1 (alpha) isoform c, KLRC3, RAB2, l-acylglycerol-3-phosphate 0-acyltransf erase 2, tryptase, alpha ^ homolog of Yeast RRP4, MCM3, hemoglobin , delta, KI 1089, zinc finger protein 44 (KOX 7), arylacetaiiiide deacetylase (esterase), synuclein, gam ma, elastase 2, neutrophil, CYP3A5, FCGR3A (CM6), likely ortholog of mouse neuralin 1, pyruvate carboxylase ^ 2 ,, 5, -ol i goadeny 1 at e synthetase 1, muscle RAS oncogene homology butyrophilin, subfamily 3, member A2, connective tissue activation peptide III, Arg / Abl-interacting protein Ar gBP2, FLJ33034, calpain 3, bleomycin hydrolase , desmuslin, TAF6L, ESTs (Accession No.AW043812), FLJ22269, kera tin 7, scaffold attachment fact 5 5; 'Nini:
or B、 KIAA0346、 interferon, alpha - inducible protein 27、 bridging integr ator 1、 および smooth muscle myosin heavy chain or B, KIAA0346, interferon, alpha-inducible protein 27, bridging integer 1, and smooth muscle myosin heavy chain
iv)群の遺伝子として好ましい遺伝子： H2B histone family, member G、 cholin ergic receptor, nicotinic, beta polypeptide 4、 related to the N terminu s of tre、 丄 aminin, gamma 2 isoform b、 interleukin 8、 K upp el-like facto r 4 (gut)、 Al strom syndrome 1、 およぴ occludin iv) Preferred genes as group genes: H2B histone family, member G, cholin ergic receptor, nicotinic, beta polypeptide 4, related to the N terminus of tre, 丄 aminin, gamma 2 isoform b, interleukin 8, K upp el- like factor 4 (gut), Al strom syndrome 1, and occludin
本発明における指標遺伝子の塩基配列、 およびこの塩基配列によってコード されるアミノ酸配列は公知である。 AD指標遺伝子の配列データを得るための Ge nBank登録番号を、 指標遺伝子の名前とともに後にまとめた。  The nucleotide sequence of the indicator gene and the amino acid sequence encoded by the nucleotide sequence in the present invention are known. The GenBank accession number for obtaining the sequence data of the AD indicator gene is summarized below along with the name of the indicator gene.
本発明のァレルギ一性疾患の検查方法は、 被検者の生体試料における各指標 遺伝子の発現レベルを測定し、 指標遺伝子が上記 a)または b)に記載された遺伝 子である場合には、 対照として同じ被検者の無疹部から採取された生体試料に おける指標遺伝子の発現レベルと、 また指標遺伝子が上記 、 d)、 c，）、 および ）のいずれかに記載された遺伝子である場合には、 対照として健常者の生体試 料における指標遺伝子の発現レベルと比較する工程を含む。 指標遺伝子が上記 a)、 、 および c' )のいずれかに記載された遺伝子であれば、 対照と比較して発 現レベルが高い場合に被検者がアトピー性皮膚炎と判定される。 また指標遺伝 子が上記！)）、 d)、 および d' )のいずれかに記載された遺伝子であれば、 対照と 比較して発現レベルが低い場合に被検者がァトピー性皮膚炎と判定される。  The method for detecting an allergic monogenic disease of the present invention measures the expression level of each indicator gene in a biological sample of a subject, and when the indicator gene is a gene described in a) or b) above, The expression level of the indicator gene in a biological sample collected from the eruption of the same subject as a control, and the indicator gene is a gene described in any of d), c,) and) above. In some cases, the method includes a step of comparing the expression level of the indicator gene in a biological sample of a healthy subject as a control. If the indicator gene is a gene described in any of the above a),, and c '), the subject is determined to be atopic dermatitis if the expression level is higher than that of the control. And the indicator gene is above! In the case of a gene described in any of)), d) and d '), a subject is judged to be atopic dermatitis if the expression level is lower than that of the control.
本発明の乾癬の検查方法「ま、 '被検者の生体試料における各指標遺伝子の発現 レベルを測定し、 指標遺伝子が上記 i)または ii)に記載された遺伝子である場 合には、 対照として同じ被検者の無疹部から採取された生体試料における指標 遺伝子の発現レベルと、 また指標遺伝子が上記 iii)または iv)に記載された遺 伝子である場合には、 対照として健常者の生体試料における指標遺伝子の発現 レベルと比較する工程を含む。 指標遺伝子が上記 i)または iii)に記載された遺 伝子であれば、 対照と比較して発現レベルが高い場合に被検者が乾癬と判定さ れる。 また指標遺伝子が上記 ii)または iv)に記載された遺伝子であれば、 対照 と比較して発現レベルが低レヽ場合に被検者が乾癬と判定される。 The psoriasis detection method of the present invention `` Well, by measuring the expression level of each indicator gene in a biological sample of a subject, and determining that the indicator gene is As a control, the expression level of the indicator gene in a biological sample collected from the eruption of the same subject, and if the indicator gene is a gene described in iii) or iv) above, a healthy control If the indicator gene is the gene described in i) or iii) above, test if the expression level is higher than that of the control. Are determined to have psoriasis It is. If the indicator gene is a gene described in ii) or iv) above, the subject is determined to be psoriasis when the expression level is lower than that in the control.
発現レベルの比較のためには、 通常、 たとえば健常者における前記指標遺伝 子の発現レベルに基づいて、 標準値が設定される。 この標準値をもとに、 たと えば ± 2 S. D.の範囲が許容範囲とされる。 指標遺伝子の測定値に基づいて、 標 準値や許容範囲を設定する手法は公知である。 あるいは、 同一患者の無疹部と の発現レベルの比較においては、 予め無疹部における指標遺伝子の発現レベル を測定して、 その患者における無疹部の標準値を決定することができる。 標準 値を設定した後には、 皮疹部の発現レベルのみを測定し、 予め決定されたその 患者の無疹部の標準値との比較に基づいて、 本発明の検査方法を実施すること もできる。  For comparison of the expression level, a standard value is usually set based on the expression level of the indicator gene in a healthy person, for example. Based on this standard value, for example, the range of ± 2 S.D. Techniques for setting a standard value and an allowable range based on a measured value of an indicator gene are known. Alternatively, in comparing the expression level with the rash-free area of the same patient, the standard value of the rash-free area in the patient can be determined by measuring the expression level of the indicator gene in the rash-free area in advance. After setting the standard value, only the expression level of the rash area is measured, and the test method of the present invention can be carried out based on a comparison with a standard value of the rash area of the patient determined in advance.
被検者における指標遺伝子が上記 a；)、 c)、 および c' )のいずれかに記載され た遺伝子である場合には、 対照と比較して発現レベルが許容範囲よりも高けれ ば、 被検者はアトピー性皮膚炎であると判定される。 同様に、 被検者における 指標遺伝子が上記 b)、 d)、 および d' )のいずれかに記載された遺伝子である場 合には、 対照と比較して発現レベルが許容範囲よりも低ければ、 被検者はアト ピー性皮膚炎であると判定される。 指標遺伝子の発現レベルが許容範囲内であ れば、 アトピー性皮膚炎である可能性は低いと予想される。  If the indicator gene in the subject is any of the genes described in any of a), c), and c ') above, the test is performed if the expression level is higher than the allowable range compared to the control. Are determined to have atopic dermatitis. Similarly, when the indicator gene in the subject is a gene described in any of b), d) and d ') above, if the expression level is lower than the allowable range compared to the control, However, the subject is determined to have atopic dermatitis. If the expression level of the indicator gene is within the acceptable range, it is expected that the possibility of atopic dermatitis is low.
被検者における指標遺伝子が上記 i)または iii)に記載された遺伝子である場 合には、 対照と比較して発現レベルが許容範囲よりも高ければ、 被検者は乾癬 であると判定される。 同様に、 被検者における指標遺伝子が上記 ii)または iv) に記載された遺伝子である場合には、 対照と比較して発現レベルが許容範囲よ りも低ければ、 被検者は乾癬であると判定される。 指標遺伝子の発現レベルが 許容範囲内であれば、 乾癬である可能性は低レ、と予想される。  If the indicator gene in the subject is the gene described in i) or iii) above, the subject is determined to have psoriasis if the expression level is higher than the acceptable level compared to the control. You. Similarly, if the indicator gene in the subject is the gene described in ii) or iv) above, the subject has psoriasis if the expression level is lower than the acceptable level compared to the control Is determined. If the expression level of the indicator gene is within the allowable range, the possibility of psoriasis is expected to be low.
本発明において、 指標遺伝子の発現レベルとは、 該指標遺伝子の mR Aへの転 写、 並びに蛋白質への翻訳を含む。 従って本発明によるアトピー性皮膚炎の検
Figure imgf000058_0001
In the present invention, the expression level of the indicator gene includes the transcription of the indicator gene into mRNA and the translation into a protein. Therefore, the detection of atopic dermatitis according to the present invention
Figure imgf000058_0001
查方法は、 指標遺伝子に対応する mRMの発現強度、 あるいは該指標遺伝子によ つてコードされる蛋白質の発現レベルの比較に基づいて行われる。 The method is performed based on a comparison of the expression intensity of mRM corresponding to the indicator gene or the expression level of the protein encoded by the indicator gene.
本努明におけるァトピー性皮膚炎または乾癬の検査における指標遺伝子の発 現レベルの測定は、 公知の遺伝子解析方法にしたがって実施することができる。 具体的には、 例えばこの遺伝子にハイブリダィズする核酸をプローブとしたハ イブリダィゼーシヨン技術、 または本発明の指標遺伝子にハイプリダイズする D NAをプライマーとした遺伝子増幅技術等を利用することができる。  The expression level of the indicator gene in the examination for atopic dermatitis or psoriasis in this effort can be measured according to a known gene analysis method. Specifically, for example, a hybridization technique using a nucleic acid that hybridizes to this gene as a probe or a gene amplification technique using DNA that hybridizes to the indicator gene of the present invention as a primer can be used. .
本癸明の検査に用いられるプローブまたはプライマーは、 指標遺伝子の塩基 配列に基づいてデザインすることができる。 指標遺伝子の塩基配列、 およぴ該 指標遺伝子によってコードされるアミノ酸配列は公知である。 本発明の各指標 遺伝子の塩基配列の GenBank ァクセシヨン番号は、 下記データ 1〜データ 4お ょぴデータ 7〜データ 1 2 (ヒト）、 およびデータ 5〜データ 6およびデータ 1 3〜データ 1 4 (マウス） に記載したとおりである。 また本発明の指標遺伝子 の一部については、 その塩基配列と塩基配列によってコードされるアミノ酸配 列を以下の配列番号に示した。 ' なお一般に高等動物の遺伝子は、 高い頻度で多型を伴う。 また、 スブライシ ングの過程で相互に異なるァミノ酸配列からなるアイソフォームを生じる分子 も多く存在する。 多型ゃァイソフォームによって塩基配列が異なる遺伝子であ つても、 指標遺伝子と同様の活性を持ち、 アトピー性皮膚炎に関与する遺伝子 は、 いずれも本発明の指標遺 子に含まれる。 Probes or primers used for the test of the present invention can be designed based on the nucleotide sequence of the indicator gene. The nucleotide sequence of the indicator gene and the amino acid sequence encoded by the indicator gene are known. GenBank Akuseshiyon number of nucleotide sequences of the marker genes of the present invention, the following data 1 data 4 Contact Yopi data 7 Data 1 2 (human), and the data 5 to data 6 and the data 1 3 - data 1 4 (Mouse ). The nucleotide sequence of a part of the indicator gene of the present invention and the amino acid sequence encoded by the nucleotide sequence are shown in the following SEQ ID NOs. 'In general, genes in higher animals are frequently associated with polymorphisms. In addition, there are many molecules that produce isoforms composed of different amino acid sequences during the sublimation process. The genes having the same activity as the indicator gene and involved in atopic dermatitis are included in the indicator gene of the present invention, even if the genes differ in base sequence depending on the polymorphic isoform.
また、 本発明において、 指標遺伝子は、 ヒ トのみならず、 他種におけるホモ ログも含む。 従って、 ヒト以外の種における指標遺伝子とは、 特に断らないと きには、 その種に固有の指標遺伝子のホモログ、 あるいはその個体に導入され ている外来性の指標遺伝子を言う。  In the present invention, the indicator gene includes not only human but also homologs of other species. Therefore, an indicator gene in a species other than human refers to a homologue of the indicator gene specific to the species or an exogenous indicator gene introduced into the individual, unless otherwise specified.
本発明においてヒト指標遺伝子のホモログとは、 ヒト指標遺伝子をプローブ としてストリンジェントな条件下でハイブリダィズすることができる、 ヒト以 外の種に由来する遺伝子を言う。 ストリンジェントな条件とは、 一般的には以 下のような条件を示すことができる。 すなわち、 4 X SSC、 65°Cでハイプリダイ ゼーシヨンさせ、 0. 1 X SSCを用いて 65°Cで 1時間洗浄する。 ストリンジェンシ 一を大きく左右するハイブリダィゼーシヨンや洗浄の温度条件は、 融解温度（T m)に応じて調整することができる。 はハイブリダィズする塩基対に占める構 成塩基の割合、 ハイプリダイゼーシヨン溶液組成 （塩濃度、 ホルムアミドゃド デシル硫酸ナトリウム濃度） によって変動する。 従って、 当業者であればこれ らの条件を考慮して同等のストリンジエンシーを与える条件を実験または経験 的に設定することができる。 In the present invention, a homologue of a human indicator gene refers to a human indicator gene that can hybridize under stringent conditions using a human indicator gene as a probe. A gene derived from a foreign species. Stringent conditions generally indicate the following conditions. That is, the cells are hybridized at 4 × SSC at 65 ° C., and washed at 65 ° C. for 1 hour using 0.1 × SSC. The temperature conditions for hybridization and washing, which greatly affect the stringency, can be adjusted according to the melting temperature (Tm). Varies depending on the ratio of constituent bases to the hybridized base pairs and the composition of the hybridization solution (salt concentration, sodium formamide-dodecyl sulfate concentration). Therefore, those skilled in the art can experimentally or empirically set conditions that give equivalent stringency in consideration of these conditions.
プライマ一あるいはプローブには、 指標遺伝子の塩基配列からなるポリヌク レオチド、 またはその相補鎖に相補的な少なくとも 15ヌクレオチドを含むポリ ヌクレオチドを利用することができる。 ここで 「相補鎖」 とは、 A:T (RNAの場 合は U)、 G: Cの塩基対からなる 2本鎖 DNAの一方の鎖に対する他方の鎖を指す。 また、 「相補的」 とは、 少なくとも 15個の連続したヌクレオチド領域で完全に 相補配列である場合に限られず、 少なくとも 70%、 好ましくは少なくとも 80%、 より好ましくは. 90%、 さらに好ましくは 95%以上の塩基配列上の相同性を有すれ ばよい。 塩基配列の相同性は、 BLAST等のアルゴリズムにより決定することがで きる。  As the primer or the probe, a polynucleotide comprising the nucleotide sequence of the indicator gene or a polynucleotide containing at least 15 nucleotides complementary to a complementary strand thereof can be used. Here, the “complementary strand” refers to one strand of the double-stranded DNA consisting of A: T (U for RNA) and G: C base pairs, relative to the other strand. The term `` complementary '' is not limited to the case where the sequence is completely complementary to at least 15 contiguous nucleotide regions, but is at least 70%, preferably at least 80%, more preferably 90%, and even more preferably 95%. It suffices to have at least the homology on the base sequence of at least%. Nucleotide sequence homology can be determined by an algorithm such as BLAST.
このようなポリヌクレオチドは、 指標遺伝子を検出するためのプローブとし て、 また指標遺伝子を増幅する'ためのプライマーとして利用することができる。 プライマーとして用いる場合には、 通常、 15bp〜100bp、 好ましくは 15bp〜35bP の鎖長を有する。 また、 プローブとして用いる場合には、 指標遺伝子 （または その相補鎖） の少なくとも一部若しくは全部の配列を有し、 少なくとも 15bpの 鎖長の DNAが用いられる。 プライマーとして用いる場合、 3'側の領域は相補的 である必要があるが、 5'側には制限酵素認識配列ゃタグなどを付加することが できる。
Figure imgf000060_0001
Such a polynucleotide can be used as a probe for detecting the indicator gene and as a primer for amplifying the indicator gene. When used as a primer, usually, 15Bp～100bp, preferably having a chain length of 15bp~35b P. When used as a probe, a DNA having at least a part or all of the sequence of the indicator gene (or its complementary strand) and having a chain length of at least 15 bp is used. When used as a primer, the 3 ′ region must be complementary, but a restriction enzyme recognition sequence tag or the like can be added to the 5 ′ region.
Figure imgf000060_0001
なお、 本発明における 「ポリヌクレオチド」 は、 DNAあるいは RNAであること ができる。 これらポリヌクレオチドは、 合成されたものでも天然のものでもよ い。 また、 ハイブリダィゼーシヨンに用いるプローブ DNAは、 通常、 標識した ものが用いられる。 標識方法としては、 例えば次のような方法を示すことがで きる。 なお用語オリゴヌクレオチドは、 ポリヌクレオチドのうち、 重合度が比 較的低いものを意味している。 オリゴヌクレオチドは、 ポリヌクレオチドに含 れる。  The “polynucleotide” in the present invention can be DNA or RNA. These polynucleotides may be synthetic or natural. The probe DNA used for hybridization is usually labeled. As the labeling method, for example, the following methods can be shown. Note that the term oligonucleotide means a polynucleotide having a relatively low degree of polymerization. Oligonucleotides are included in polynucleotides.
. DNAポリメラーゼ Iを用いるニックトランスレーションによる標識  Labeling by nick translation using DNA polymerase I
•ポリヌクレオチドキナーゼを用いる末端標識  • End labeling using polynucleotide kinase
'クレノーフラグメントによるフィルィン末端標識 （Berger SL， Ki丽 el AR. (1987) Guide to Molecular Cloning Techniques, Method in Enzymology, Aca demic Press; Hames BD, Higgins SJ (1985) Genes Probes： A Practical Appr oach. IRL Press； Sambrook J, Fritsch EF, Maniatis T. (1989) Molecular C 丄 oning: a Laboratory Manual, 2nd Edn. Cold Spring Harbor Laboratory Pre ss)  'Filin end labeling with Klenow fragment (Berger SL, Kiel el. (1987) Guide to Molecular Cloning Techniques, Method in Enzymology, Aca demic Press; Hames BD, Higgins SJ (1985) Genes Probes: A Practical Approach. IRL Press; Sambrook J, Fritsch EF, Maniatis T. (1989) Molecular C oning: a Laboratory Manual, 2nd Edn. Cold Spring Harbor Laboratory Press)
• RNAポリメラーゼを用いる転写による標識 （Melton DA， Krieg, PA, Rebagkiat i MR, Maniatis T， Zinn K, Green MR. (1984) Nucleic Acid Res. , 12， 7035-7 056)  • Labeling by transcription using RNA polymerase (Melton DA, Krieg, PA, Rebagkiat i MR, Maniatis T, Zinn K, Green MR. (1984) Nucleic Acid Res., 12, 7035-7 056)
•放射性同位体を用いない修飾ヌクレオチドを DNAに取り込ませる方法 （Krick a LJ. (1992) Nonisotopic DNA Probing Tecnniques. Academic Press  • Incorporation of modified nucleotides without radioisotopes into DNA (Krick a LJ. (1992) Nonisotopic DNA Probing Tecnniques. Academic Press
ハイプリダイゼーション技術を利用したアトピー性皮膚炎の検査は、 例えば、 ノ一ザンノヽィブリダイゼーション法、 ドットプロット法、 DNAマイクロアレイを 用いた方法などを使用して行うことができる。 さらには、 RT - PCR法等の遺伝子 増幅技術を利用することができる。 RT- PCR法においては、 遺伝子の増幅過程に おいて PCR増幅モニター法を用いることにより、 本発明の指標遺伝子の発現に ついて、 より定量的な解析を行うことが可能である。 PCR遺伝子増幅モニター法においては、 両端に互いの蛍光を打ち消し合う異な つた蛍光色素で標識したプローブを用い、 検出対象 (DNAもしくは RNAの逆転写 産物） にハイブリダィズさせる。 PCR反応が進んで Taqポリメラ一ゼの 5' -3'ェ キソヌクレアーゼ （exonuclease) 活性により同プロープが分解されると二つの 蛍光色素が離れ、 蛍光が検出されるようになる。 この蛍光の検出をリアルタイ ムに行う。 検出対象についてコピー数の明らかな標準試料について同時に測定 することにより、 PCR増幅の直線性のあるサイクル数で目的試料中の検出対象の コピー数を決定する （Holland, P. M. et al. , 1991, Proc. Natl. Acad. Sci. USA 88: 7276 - 7280; Livak, K. J. et al. , 1995, PCR Methods and Applicatio ns 4(6) : 357-362； He id, C. A. et al. , Genome Research 6: 986-994; Gibson, E, M. U. et al. , 1996， Genome Research 6: 995 - 1001)。 PCR増幅モニター法 においては、 例えば、 ABI PRISM7700 (Applied Biosystems ¾h) を用いることが できる。 The test for atopic dermatitis using the hybridization technique can be performed using, for example, a Northern hybridization method, a dot plot method, a method using a DNA microarray, and the like. Furthermore, gene amplification techniques such as the RT-PCR method can be used. In the RT-PCR method, the expression of the indicator gene of the present invention can be analyzed more quantitatively by using the PCR amplification monitoring method in the gene amplification process. In the PCR gene amplification monitoring method, probes that are labeled with different fluorescent dyes that cancel each other's fluorescence on both ends are used to hybridize to the detection target (reverse transcript of DNA or RNA). As the PCR proceeds and the 5'-3 'exonuclease activity of Taq polymerase decomposes the probe, the two fluorescent dyes are separated and fluorescence is detected. This fluorescence is detected in real time. The number of copies of the target in the target sample is determined based on the number of linear cycles of PCR amplification by simultaneously measuring a standard sample with a clear copy number for the target (Holland, PM et al., 1991, Proc. Natl. Acad. Sci. USA 88: 7276-7280; Livak, KJ et al., 1995, PCR Methods and Applications 4 (6): 357-362; Heid, CA et al., Genome Research 6: 986. -994; Gibson, E, MU et al., 1996, Genome Research 6: 995-1001). In the PCR amplification monitoring method, for example, ABI PRISM7700 (Applied Biosystems ¾h) can be used.
また本発明のアトピー性皮膚炎または乾癬の検査方法は、 指標遺伝子により コードされる蛋白質を検出することにより行うこともできる。 このような検査 方法としては、 例えば、 各指標蛋白質に結合する抗体を利用したウェスタンブ ロッテイング法、 免疫沈降法、 ELISA法などを利用することができる。  Further, the method for testing atopic dermatitis or psoriasis of the present invention can also be performed by detecting a protein encoded by an indicator gene. As such a test method, for example, a Western blotting method, an immunoprecipitation method, an ELISA method, or the like using an antibody that binds to each indicator protein can be used.
この検出に用いる指標蛋白質に結合する抗体は、 当業者に周知の技法を用い て得ることができる。 本発明に用いる抗体は、 ポリクローナル抗体、 あるいは モノクローナル抗体 (Milstein C, et al. , 1983, Nature 305 (5934)： 537 - 40) であることができる。 例えば、 指標蛋白質に対するポリクローナル抗体は、 抗 原を感作した哺乳動物の血液を取り出し、 この血液から公知の方法により血清 を分離する。 ポリクローナル抗体としては、 ポリクローナル抗体を含む血清を 使用することができる。 あるいは必要に応じてこの血清からポリクローナル抗 体を含む画分をさらに単離することもできる。 また、 モノクローナル抗体を得 るには、 上記抗原を感作した哺乳動物から免疫細胞を取り出して骨髄腫細胞な ―Antibodies that bind to the indicator protein used for this detection can be obtained using techniques well known to those skilled in the art. The antibody used in the present invention can be a polyclonal antibody or a monoclonal antibody (Milstein C, et al., 1983, Nature 305 (5934): 537-40). For example, a polyclonal antibody against an indicator protein is obtained by extracting blood of a mammal sensitized with an antigen and separating serum from the blood by a known method. As the polyclonal antibody, serum containing the polyclonal antibody can be used. Alternatively, if necessary, a fraction containing a polyclonal antibody can be further isolated from the serum. To obtain a monoclonal antibody, immunocytes are removed from a mammal sensitized with the above antigen and myeloma cells or the like are extracted. ―
O 2004/0313，。8，6 O 2004/0313 ,. 8,6
6 1； 」 6 1;
どと細胞融合させる。 こうして得られたハイブリ ドーマをクローニングして、 その培養物から抗体を回収しモノクローナル抗体とすることができる。 Cell fusion. The hybridoma thus obtained is cloned, and the antibody is recovered from the culture to obtain a monoclonal antibody.
指標蛋白質の検出には、 これらの抗体を適宜標識して用いればよい。 また、 この抗体を標識せずに、 該抗体に特異的に結合する物質、 例えば、 プロテイン A やプロテイン G を標識して間接的に検出することもできる。 具体的な検出方法 としては、 例えば、 ELISA法を挙げることができる。  These antibodies may be appropriately labeled and used for detection of the indicator protein. In addition, without labeling the antibody, a substance that specifically binds to the antibody, for example, protein A or protein G can be labeled and detected indirectly. As a specific detection method, for example, an ELISA method can be mentioned.
抗原に用いる蛋白質もしくはその部分べプチドは、 例えば指標遺伝子もしく はその一部を発現ベクターに組込み、 これを適当な宿主細胞に導入して、 形質 転換体を作成し、 該形質転換体を培養して組み換え蛋白質を発現させ、 発現さ せた組み換え蛋白質を培養体または培養上清から精製することにより得ること ができる。 あるいは、 該遺伝子によってコードされるアミノ酸配列、 あるいは 全長 cDNAによってコードされるアミノ酸配列の部分アミノ酸配列からなるオリ ゴペプチドを化学的に合成し、 免疫原として用いることもできる。  A protein or a partial peptide thereof used as an antigen can be obtained by, for example, incorporating an indicator gene or a part thereof into an expression vector, introducing this into an appropriate host cell, preparing a transformant, and culturing the transformant. Then, the recombinant protein is expressed, and the expressed recombinant protein can be obtained by purifying it from a culture or a culture supernatant. Alternatively, an oligopeptide consisting of the amino acid sequence encoded by the gene or a partial amino acid sequence of the amino acid sequence encoded by the full-length cDNA can be chemically synthesized and used as an immunogen.
更に本発明においては、 指標遺伝子の発現レベルのみならず、 生体試料にお ける指標蛋白質の活性を指標として、 アレルギー性疾患または乾癬の検査を行 うこともできる。 指標蛋白質の活性とは、 該蛋白質が備える生物学的な活性を 言う。 以下に各蛋白質の有する活性を測定するための一般的な方法を記載する。  Further, in the present invention, allergic diseases or psoriasis can be tested using not only the expression level of the indicator gene but also the activity of the indicator protein in a biological sample as an indicator. The activity of the indicator protein refers to the biological activity of the protein. Hereinafter, a general method for measuring the activity of each protein will be described.
[プロテアーゼ]  [Protease]
プロテアーゼサンプルをゼラチンなどの基質を共重合させた SDS ポリアクリ ルアミドゲルで非還元条件下に電気泳動を行い、 泳動後に至適緩衝液中で 37°C、 16時間静置する。 16時間後にクマシープリリアントブルー R250でゲルを染色し、 プロテア一ゼの泳動位置が染色されないこと、 すなわちゼラチンが分解されて いることでプロテアーゼ活性を評価できる。  Perform electrophoresis of the protease sample on a SDS polyacrylamide gel obtained by copolymerizing a substrate such as gelatin under non-reducing conditions. After the electrophoresis, allow the protease sample to stand in the optimal buffer at 37 ° C for 16 hours. Sixteen hours later, the gel is stained with Coomassie Priliant Blue R250, and the protease activity can be evaluated based on the fact that the migration position of the protease is not stained, that is, the gelatin is degraded.
Chen, J. M.ら J. Biol. Chem. 266, 5113-5121 (1991) Chen, J. M. et al. J. Biol. Chem. 266, 5113-5121 (1991)
[プロテアーゼィンヒビター]  [Protease inhibitor]
プロテアーゼインヒビターをゼラチンなどのプロテア一ゼ基質を共重合させ た SDS ポリアクリルアミドゲルで非還元条件下に電気泳動を行い、 泳動後にプ 口テアーゼを添加した至適緩衝液中で 37°C、 16時間静置する。 16時間後にクマ シーブリリアントブルー R250 でゲルを染色し、 プロテアーゼインヒビターの泳 動位置が染色されていること、 すなわちゼラチンが分解されていないことでプ 口テアーゼィンヒビター活性を評価できる。 Protease inhibitor is copolymerized with a protease substrate such as gelatin. Perform electrophoresis on the SDS polyacrylamide gel under non-reducing conditions, and after the electrophoresis, allow to stand at 37 ° C for 16 hours in the optimal buffer solution supplemented with protease. Sixteen hours later, the gel is stained with bear sieve brilliant blue R250, and the protease inhibitor swimming activity is stained, that is, the gelatin is not degraded, so that the protease inhibitor activity can be evaluated.
Greene Jら J. Biol. Chem. 271， 30375 - 30380 (1996) Greene J et al. J. Biol. Chem. 271, 30375-30380 (1996).
[転写因子]  [Transcription factor]
転写因子を 32Pなどで標識した転写因子の標的配列を含む 2本鎖ォリゴ DNAと 共に室温でィンキュベートして結合させる。 ィンキュベート後のサンプルは SDS を含まない未変性ポリアクリルアミドゲルで電気泳動を行い、 標識したオリゴ!） NAの移動度を 32Pの放射活性などを指標にして評価する。 転写因子にオリゴ DNA に対する結合活性があれば、 標識したオリゴ DM の移動度が遅くなり、 高分子 量側にシフトする。 標的配列に対する結合特異性は、 過剰量の標識をしていな い 2本鎖オリゴ DNAにより転写因子と標識オリゴ DNA の結合が阻害されること により確認できる。 The transcription factor is incubated with double-stranded oligo DNA containing the target sequence of the transcription factor labeled with 32 P or the like at room temperature to bind. The sample after the incubation is subjected to electrophoresis on a non-denaturing polyacrylamide gel containing no SDS, and the mobility of the labeled oligo!) NA is evaluated using the radioactivity of 32 P as an index. If the transcription factor has an activity to bind to oligo DNA, the mobility of the labeled oligo DM becomes slow and shifts to higher molecular weight. The binding specificity for the target sequence can be confirmed by inhibiting the binding between the transcription factor and the labeled oligo DNA by an excessive amount of unlabeled double-stranded oligo DNA.
また、 転写因子による転写活性化能は、 レポーター遺伝子発現ベクターと、 転写因子発現べクタ一の共形質転換によって、 当該転写因子の活性を評価する ことができる。 レポーター遺伝子発現ベクターは、 その標的配列の下流にクロ ラムフエニコールァセチルトランスフェラーゼ （CAT) などのレポーター遺伝子 を連結した発現ベクターである。 一方、 活性を評価すべき転写因子は、 転写因 子遺伝子をヒ トサイ トメガロウィルス （CMV) の応答遺伝子プロモーターなどの 下流に連結した転写因子発現べクタ一によつて発現させることができる。 これ らのべクターを、 Helaや HEK293などの細胞株に共遺伝子導入し、 4 8時間後に 細胞破碎液を調製して CAT の発現量を調べることにより転写活性を評価できる。 Zhao Fら J. Biol. Chem. 276, 40755 - 40760 (2001)  In addition, the ability to activate transcription by a transcription factor can be evaluated for the activity of the transcription factor by co-transformation of a reporter gene expression vector and a transcription factor expression vector. A reporter gene expression vector is an expression vector in which a reporter gene such as chloramphenicol acetyltransferase (CAT) is linked downstream of its target sequence. On the other hand, a transcription factor whose activity is to be evaluated can be expressed by a transcription factor expression vector in which a transcription factor gene is linked downstream, such as a human cytomegalovirus (CMV) response gene promoter. These vectors can be co-transfected into cell lines such as Hela and HEK293, and 48 hours later, cell lysates can be prepared and the expression level of CAT can be examined to evaluate the transcription activity. Zhao F et al. J. Biol. Chem. 276, 40755-40760 (2001)
[キナーゼ] キナーゼを myelin basic proteinを基質として含む緩衝液 (20 mM HEPES, p H7. 5, 10 mM MgCl2, 2 niM MnCl2, 2 mM dithiothreitol, and 25 ATP) に添 加し、 更に [ γ - 32P]ATPを添加して 37°Cで 10分保温する。 10分後に Lae鹿 li緩 衝液で反応を止め、 反応液を SDS ポリアクリルアミドゲル電気泳動に供し、 泳 動後にゲルを乾燥させてリン酸化された myelin basic proteinの放射活性を X 線フィルムにて検出する。 [Kinase] Buffer containing kinases myelin basic protein as substrate (. 20 mM HEPES, p H7 5, 10 mM MgCl 2, 2 niM MnCl 2, 2 mM dithiothreitol, and 25 ATP) was added to warm to further [gamma - 32 P ] Add ATP and incubate at 37 ° C for 10 minutes. After 10 minutes, stop the reaction with Lae deer buffer solution, subject the reaction solution to SDS polyacrylamide gel electrophoresis, dry the gel after swimming, and detect the radioactivity of phosphorylated myelin basic protein on X-ray film I do.
Park SYら J. Biol. Chem. 275, 19768 - 19777 (2000)  Park SY et al. J. Biol. Chem. 275, 19768-19777 (2000)
[フォスファターゼ]  [Phosphatase]
フォスファターゼを p- nitrophenyl phosphate (pNPP)を基質として含む緩衝 液 （25 mM MES, H 5. 5, 1. 6 mM dithiothreitol, 10 mM pNPP) に添加し、 3 7°Cで 30分間保温する。 30分後に IN NaOHを添加して反応を停止し、 pNPPの加 水分解の結果生じた 405nmの吸光度を測定する。  Add phosphatase to a buffer solution (25 mM MES, H 5.5, 1.6 mM dithiothreitol, 10 mM pNPP) containing p-nitrophenyl phosphate (pNPP) as a substrate, and incubate at 37 ° C for 30 minutes. After 30 minutes, the reaction is stopped by adding IN NaOH, and the absorbance at 405 nm resulting from the hydrolysis of pNPP is measured.
Aoyama Kら J. Biol. Chem. 276, 27575-27583 (2001) Aoyama K et al. J. Biol. Chem. 276, 27575-27583 (2001)
[ケモカイン、 ケモカインレセプター]  [Chemokine, chemokine receptor]
ケモカインレセプターを強制発現させた細胞を、 カルシウム感受性蛍光色素 f ura-2を含む Hank' s balanced salt solutionに懸濁し、 ケモカインにより刺激 を加える。 ケモカイン刺激により引き起こされる細胞内カルシウム濃度の上昇 を LS50B (PerkinElmer) などの蛍光検出器で測定する。  The cells in which the chemokine receptor is forcibly expressed are suspended in Hank's balanced salt solution containing a calcium-sensitive fluorescent dye fura-2, and stimulated with a chemokine. The increase in intracellular calcium concentration caused by chemokine stimulation is measured with a fluorescence detector such as LS50B (PerkinElmer).
Zhou Nら J. Biol. Chem. 276， 42826-42833 (2001) Zhou N et al. J. Biol. Chem. 276, 42826-42833 (2001).
[サイトカイン、 サイトカインレセプター]  [Cytokine, cytokine receptor]
サイトカインでサイトカインレセプターを発現する細胞を刺激し、 これによ り引き起こされる細胞増殖をチミジンの取り込みで評価する。  Cells that express the cytokine receptor are stimulated with cytokines, and the cell proliferation caused by the stimulation is assessed by thymidine incorporation.
または、 サイトカイン刺激によるサイトカインレセプター下流に位置する転 写因子の活性化をルシフェラーゼなどのレポータ一遺伝子の発現により評価す ることもできる。  Alternatively, activation of a transcription factor located downstream of a cytokine receptor by cytokine stimulation can be evaluated by expression of a reporter gene such as luciferase.
Piek Eら J. Biol. Chem. 276， 19945 - 19953 (2001) [イオンチャンネル] Piek E et al. J. Biol. Chem. 276, 19945-19953 (2001) [Ion channel]
先端の開口径が数; i m2のガラスピぺットの先端にイオンチャンネルを含む形 質膜を貼り付け、 ピぺット內外に電位差を与えてその時にチャンネルを通る電 流を測定するパッチクランプ法により評価できる。 A patch clamp that attaches a membrane containing an ion channel to the tip of the glass pipe of im 2 and gives a potential difference outside the pipe to measure the current passing through the channel at that time. It can be evaluated by the method.
Hamill, 0. P.ら Pfluegers Arch. 391, 85—100 (1981) Hamill, 0. P. et al. Pfluegers Arch. 391, 85-100 (1981)
[細胞接着因子]  [Cell adhesion factor]
細胞表面に接着分子を発現させた細胞をそのリガンドをコ一トしたプレート 上でインキュベートし、 接着した鉀胞数を評価する。  Cells expressing the adhesion molecule on the cell surface are incubated on a plate coated with the ligand, and the number of adhered cells is evaluated.
Fujiwara Hら J. Biol. Chem. 276, 17550-17558 (2001) Fujiwara H et al. J. Biol. Chem. 276, 17550-17558 (2001).
[細胞外マトリックス蛋白質]  [Extracellular matrix protein]
細胞外マトリックス蛋白質をコートしたプレートにインテグリンなどの細胞 外マトリックス蛋白質に対する受容体を持つ細胞の懸濁液を加え、 37°Cで 1 時 間培養する。 培養後に細胞を固定し、 Hoechst 33342などの DNA結合性蛍光色素 を加えて反応させる。 反応後にフルォロメーターを使用して蛍光強度を測定し、 蛍光強度として定量化された接着細胞数を細胞外マトリックス蛋白質の活性と して評価する。  Add a cell suspension containing receptors for extracellular matrix proteins such as integrins to the plate coated with extracellular matrix proteins, and incubate at 37 ° C for 1 hour. After culturing, fix the cells and add a DNA-binding fluorescent dye such as Hoechst 33342 to react. After the reaction, the fluorescence intensity is measured using a fluorimeter, and the number of adherent cells quantified as the fluorescence intensity is evaluated as the activity of extracellular matrix protein.
Miyazaki Kら Proc. Natl. Acad. Sci. U. S. A. 90, 11767 (1993)  Miyazaki K et al. Proc. Natl. Acad. Sci. U.S.A. 90, 11767 (1993)
本発明の検查方法においては、 被検者の皮膚組織を試料とする。 皮膚組織試 料の採取は、 被検者に多少の痛みを伴う。 一方で、 皮膚組織は容易に採取でき るため、 診断材料としては有用である。  In the detection method of the present invention, the skin tissue of the subject is used as a sample. The collection of skin tissue samples is somewhat painful to the subject. On the other hand, skin tissue can be easily collected and is useful as a diagnostic material.
皮膚組織を採取する方法は公知である。 皮膚組織は、 例えば次のようにして 採取することができる。 すなわち、 まず、 局所麻酔薬により採取部位を麻酔す る。 生検個所の周囲の皮膚を引っ張ってたるみの無い状態とした後、 パンチを 皮膚の中に埋め込み、 回転させて標本分の組織をパンチの中に入れる。 パンチ を引き出し、 切り取られたパンチ内の皮膚を回収する。 パンチは、 中空の皮膚 組織採取用の器具である。 たとえば直径 3 mmの皮膚組織の採取が可能な器具が 一般に利用されている。 Methods for collecting skin tissue are known. Skin tissue can be collected, for example, as follows. That is, the sampling site is first anesthetized with a local anesthetic. After pulling the skin around the biopsy site to make it slack-free, embed the punch in the skin and rotate it to insert the tissue of the specimen into the punch. Pull out the punch and collect the cut skin inside the punch. A punch is a hollow skin tissue sampling device. For example, a device that can collect skin tissue with a diameter of 3 mm It is commonly used.
本発明において、 皮膚組織とは、 解剖学的には表皮および真皮を含む。 皮膚 組織には、 皮膚固有の細胞のみならず、 リンパ球、 ランゲルハンス細胞、 ある いはマスト細胞などの、 皮膚組織において見出される皮膚以外の細胞が含まれ る場合がある。 これらの皮膚細胞とともに採取される細胞も皮膚組織試料に含 まれる。  In the present invention, the skin tissue anatomically includes the epidermis and the dermis. Skin tissue can include non-skin cells found in skin tissue, such as lymphocytes, Langerhans cells, or mast cells, as well as cells specific to the skin. Cells collected together with these skin cells are also included in skin tissue samples.
本発明において、 皮疹部における指標遺伝子の発現レベルを決定するために、 皮疹部の皮膚組織試料が用いられる。 皮疹部とは、 急性病変を形成している皮 膚を言う。 たとえば日本皮膚科学会誌 104： 1210 (1994) に報告されている診断 基準にしたがって、 急性病変部を判定することができる。 具体的には、 たとえ ば次のような臨床所見が急性病変部の指標とされている。  In the present invention, a skin tissue sample from the rash is used to determine the expression level of the indicator gene in the rash. The rash is the skin that forms the acute lesion. For example, acute lesions can be determined according to the diagnostic criteria reported in Japanese Dermatological Association 104: 1210 (1994). Specifically, for example, the following clinical findings are used as indicators of acute lesions.
急性病変：紅斑、 湿潤性紅斑、 丘疹、 漿液性丘疹、 鱗屑、 痂皮  Acute lesions: erythema, wet erythema, papules, serous papules, scales, crusts
また患者の無疹部における指標遺伝子の発現レベルを決定するために、 無瘆 部の皮膚組織試料が用いられる。 患者における無疹部とは、 上記病変を伴わな い部位の皮膚である。 更に、 健常者の皮膚における指標遺伝子の発現レベルを 決定するには、 健常者の皮膚組織が用いられる。 本発明における健常者とは、 診断すべき疾患を有していないことが明らかなヒトを言う。 すなわちアレルギ 一性疾患の検査においてはアレルギー性疾患を有していないヒトが健常者であ る。 同様に、 乾癬の検査方法においては乾癬を有していないヒトが健常者であ る。 健常者は、 診断すべき 患以外の疾患を有することが許容される。 しかし、 好ましい健常者は、 アレルギー性疾患および乾癬のいずれをも有していないヒ トである。 皮膚組織の採取は、 患者の皮膚組織の採取と同様の手法によって採 取することができる。 指標遺伝子の発現レベルの比較においては、 できるだけ 同じ部位の皮膚を比較するのが望ましい。 しかし同一患者の皮疹部/無疹部の 比較においては、 同じ部位に無疹部の皮膚を見出すのが困難であるケースも予 想される。 このようなケースでは、 異なる部位の皮膚を比較に用いることもで きる。 Further, in order to determine the expression level of the indicator gene in a rash-free area of a patient, a skin tissue sample of the rash-free area is used. The eruption in the patient is the skin at a site not accompanied by the above lesion. Furthermore, to determine the expression level of the indicator gene in the skin of a healthy subject, the skin tissue of a healthy subject is used. The healthy subject in the present invention refers to a human who clearly has no disease to be diagnosed. That is, in testing for allergic diseases, humans without allergic diseases are healthy subjects. Similarly, in the test method for psoriasis, a person without psoriasis is a healthy subject. A healthy person is allowed to have a disease other than the disease to be diagnosed. However, preferred healthy individuals are those who have neither allergic disease nor psoriasis. The skin tissue can be collected by the same method as the collection of the patient's skin tissue. When comparing the expression levels of the indicator genes, it is desirable to compare skin at the same site as much as possible. However, in the comparison of the rash / rash-free area of the same patient, it may be difficult to find the rash-free skin at the same site. In such cases, skin from different sites can be used for comparison. Wear.
皮膚組織試料の採取は容易であるため、 医療現場における簡便な検査が可能 である。 例えば、 実施例に示す方法によって調製することができる。 調製され た皮膚組織を破壌してライセートとすれば、 指標蛋白質の免疫学的な測定のた めの試料とすることができる。  Since the collection of skin tissue samples is easy, simple examinations at medical sites are possible. For example, it can be prepared by the method shown in Examples. If the prepared skin tissue is lysed into lysate, it can be used as a sample for immunological measurement of the indicator protein.
上記の生体試料からライセートを調製すれば、 指標蛋白質の免疫学的な測定 のための試料とすることができる。 あるいはこのライセートから mRNAを抽出す れば、 指標遺伝子に対応する mR Aの測定のための試料とすることができる。 生 体試料のライセートまたは mRNAの抽出には、 市販のキットを利用すると便利で ある。 また指標蛋白質が血中に分泌されていれば、 被検者の血液や血清などの 体液試料に含まれる目的とする蛋白質の量を測定することによって、 それをコ ードする遺伝子の発現レベルの比較が可能である。 上記試料は、 必要に応じて 緩衝液等で希釈して本発明の方法に使用することができる。  If a lysate is prepared from the above biological sample, it can be used as a sample for immunological measurement of the indicator protein. Alternatively, if mRNA is extracted from this lysate, it can be used as a sample for measuring mRNA corresponding to the indicator gene. It is convenient to use commercially available kits for extracting lysates or mRNA from biological samples. If the indicator protein is secreted into the blood, the expression level of the gene encoding the protein can be measured by measuring the amount of the target protein contained in a body fluid sample such as blood or serum of the subject. Comparison is possible. The above sample can be diluted with a buffer or the like, if necessary, and used in the method of the present invention.
mRNA を測定する場合には、 本発明における指標遺伝子の発現レベルの測定値 は、 公知の方法によって補正することができる。 補正により、 細胞における遺 伝子の発現レベルの変化を比較することができる。 測定値の補正は、 上記生体 試料における各細胞において、 発現レベルが大きく変動しない遺伝子 （例えば、 ハウスキーピング遺伝子） の発現レベルの測定値に基づいて、 本発明において 指標遺伝子の発現レベルの測定値を補正することによって行われる。 発現レべ ルが大きく変動しない遺伝 の例としては、 -ァクチン、 GAPDH等を挙げるこ とができる。  When measuring mRNA, the measured value of the expression level of the indicator gene in the present invention can be corrected by a known method. With the correction, changes in the expression level of the gene in the cells can be compared. In the present invention, the measurement value is corrected based on the measurement value of the expression level of a marker gene (for example, a housekeeping gene) whose expression level does not fluctuate greatly in each cell in the biological sample. This is done by correcting. Examples of the gene whose expression level does not fluctuate greatly include -actin, GAPDH and the like.
更に本発明は、 本発明の検査方法のための試薬を提供する。 すなわち本発明 は、 指標遺伝子の塩基配列を含むポリヌクレオチド、 またはその相補鎖に相補 的な塩基配列を有する少なくとも 1 5塩基の長さを有するオリゴヌクレオチド からなる、 アトピー性皮膚炎の検査用試薬に関する。 あるいは本発明は、 指標 蛋白質を認識する抗体からなる、 アトピー性皮膚炎の検査用試薬に関する。 本 発明の試薬を構成するオリゴヌクレオチドや抗体は、 アツセィフォーマツトに 応じて適当な標識を結合することができる。 あるいは本発明の試薬を構成する オリゴヌクレオチドや抗体は、 アツセィフォーマットに応じて適当な支持体に 固定化しておくこともできる。 また本発明の試薬は、 前記オリゴヌクレオチド または前記抗体の他に、 検査や保存に必要な付加的な要素と組み合せて検查用 キットとすることもできる。 キットを構成することができる付加的な要素を、 以下に示す。 これらの要素は、 必要に応じて予め混合しておくこともできる。 また、 必要に応じて、 保存剤や防腐剤を各要素に加えることができる。 Further, the present invention provides a reagent for the test method of the present invention. That is, the present invention relates to a test reagent for atopic dermatitis, comprising a polynucleotide containing a base sequence of an indicator gene or an oligonucleotide having a base sequence complementary to a complementary strand thereof and having a length of at least 15 bases. . Alternatively, the present invention relates to a reagent for testing atopic dermatitis, comprising an antibody that recognizes an indicator protein. Book Oligonucleotides and antibodies constituting the reagent of the present invention can be bound with an appropriate label according to the assay format. Alternatively, the oligonucleotide or antibody constituting the reagent of the present invention can be immobilized on a suitable support according to the Atsey format. In addition, the reagent of the present invention can be used as a test kit by combining the oligonucleotide or the antibody with additional components necessary for testing and storage. Additional components that can make up the kit are shown below. These components can be pre-mixed if necessary. If necessary, preservatives and preservatives can be added to each element.
試薬や生体試料を希釈するための緩衝液  Buffer for diluting reagents and biological samples
陽性対照  Positive control
陰性対照  Negative control
標識を測定するための基質  Substrates for measuring labels
反応容器  Reaction vessel
アツセィプロトコルを記載した指示書  Instructions describing Atsushi protocol
本発明における AD指標遺伝子は、 アトピー性皮膚炎患者の皮疹部と同一の患 者における無疹部、 あるいはアトピー性皮膚炎患者の無疹部と健常者との比較 において、 各皮膚組織において発現量の変動が確認された。 従って、 AD指標遺 伝子の発現レベルを指標として、 ァトピー性皮膚炎の検査を行うことができる。 本発明におけるアトピー性皮膚炎の検査とは、 たとえば以下のような検査が 含まれる。 アトピー性皮膚炎が'疑われる症状を示しながら、 一般的な検査では アトピー性皮膚炎と判定できない患者であっても、 本発明に基づく検査を行え ばァトピー性皮膚炎の患者であるか否かを容易に判定することができる。 より 具体的には、 アトピー性皮膚炎が疑われる症状を示す患者において、 AD指標遺 伝子が a)、 c)、 および c' )のいずれかに記載された遺伝子である場合、 AD指標 遺伝子の発現の上昇は、 その症状の原因がアトピー性皮膚炎である可能性が高 いことを示している。 また、 アトピー性皮膚炎が疑われる症状を示す患者にお いて、 AD指標遺伝子が b)、 d)、 および d' )のいずれかに記載された遺伝子であ る場合、 AD指標遺伝子の発現の低下は、 その症状の原因が同じくアトピー性皮 膚炎である可能性が高いことを示している。 The expression level of the AD indicator gene in the present invention is expressed in each skin tissue in a rash-free area in the same patient as the rash in an atopic dermatitis patient, or in a comparison between a rash-free area in an atopic dermatitis patient and a healthy subject. Was confirmed. Therefore, atopic dermatitis can be tested using the expression level of the AD indicator gene as an indicator. The test for atopic dermatitis in the present invention includes, for example, the following tests. Even if a patient can not determine atopic dermatitis by general examination while showing symptoms that atopic dermatitis is suspected, if the test based on the present invention is performed, whether the patient is a patient with atopic dermatitis Can be easily determined. More specifically, when the AD indicator gene is a gene described in any of a), c), and c ') in a patient exhibiting symptoms of suspected atopic dermatitis, the AD indicator gene Increased expression indicates that the cause of the condition is likely to be atopic dermatitis. In addition, patients with symptoms of suspected atopic dermatitis When the AD indicator gene is a gene described in any of b), d), and d '), a decrease in the expression of the AD indicator gene is caused by atopic dermatitis, which is also caused by the symptoms. It indicates that there is a high possibility.
あるいは、 アトピー性皮膚炎が改善に向かっているのかどうかを判断するた めの検査が可能となる。 つまり、 アトピー性皮膚炎に対する治療効果の判定に 有用である。 また、 アトピー性皮膚炎と診断された患者において、 AD指標遺伝 子が a)、 、 および c )のいずれかに記載された遺伝子である場合、 AD指標遺 伝子の発現の上昇は、 アトピー性皮膚炎がさらに進行している可能性が高いこ とを示している。 また、 アトピー性皮膚炎と診断された患者において、 AD指標 遺伝子が b)、 d)、 および d' )のいずれかに記載された遺伝子である場合、 AD指 標遺伝子の発現の低下は、 同じくアトピー性皮膚炎がさらに進行している可能 性が高いことを示している。  Alternatively, tests can be performed to determine if atopic dermatitis is improving. In other words, it is useful for judging the therapeutic effect on atopic dermatitis. In addition, in patients diagnosed with atopic dermatitis, when the AD indicator gene is a gene described in any of a),, and c), the increase in expression of the AD indicator gene is This indicates that dermatitis is likely to be more advanced. In addition, in patients diagnosed with atopic dermatitis, when the AD indicator gene is any of b), d), and d '), the decrease in the expression of the AD indicator gene is also This indicates that atopic dermatitis is likely to be more advanced.
更に、 発現レベルの違いに基づいてァトピー性皮膚炎の重症度を判定するこ ともできる。 すなわち、 AD指標遺伝子が a)、 、 および c' )のいずれかに記载 された遺伝子である場合、 AD指標遺伝子の発現の上昇の程度は、 アトピー性皮 膚炎の重症度に相関する。 あるいは AD指標遺伝子が b)、 d)、 および d' )のいず れかに記載された遺伝子である場合、 AD指標遺伝子の発現の低下の程度が、 ァ トピー性皮膚炎の重症度に相関する。  Furthermore, the severity of atopic dermatitis can be determined based on the difference in expression level. That is, when the AD indicator gene is a gene described in any of a), c)), the degree of increase in the expression of the AD indicator gene correlates with the severity of atopic dermatitis. Alternatively, when the AD indicator gene is any of the genes listed in b), d) and d '), the degree of decrease in the expression of the AD indicator gene correlates with the severity of atopic dermatitis I do.
—方本発明における乾癬指標遺伝子は、 乾癬患者の皮疹部と同一の患者にお ける無疹部、 あるいは乾癬急者の無疹部と健常者との比較において、 各皮膚組 織において発現量の変動が確認された。 従って、 乾癬指標遺伝子の発現レベル を指標として、 乾癬の検查を行うことができる。  The expression level of the psoriatic index gene in the present invention is expressed in each skin tissue in comparison between the eruption area of the same patient as the rash area of a psoriasis patient or the rash area of an acute psoriasis patient and a healthy subject. Fluctuation was confirmed. Therefore, psoriasis can be detected using the expression level of the psoriasis indicator gene as an indicator.
本発明における乾癬の検査とは、 たとえば以下のような検査が含まれる。 乾 癬が疑われる症状を示しながら、 一般的な検査では乾癬と判定できない患者で あっても、 本発明に基づく検查を行えば乾癬の患者であるか否かを容易に判定 することができる。 より具体的には、 乾癬が疑われる症状を示す患者において、 PThe test for psoriasis in the present invention includes, for example, the following tests. Even if a patient cannot be determined to be psoriasis by a general test while showing symptoms suspected of psoriasis, the test according to the present invention can easily determine whether or not the patient is a psoriasis patient. . More specifically, in patients with symptoms suspected of psoriasis, P
O 2004/031386 O 2004/031386
6 9; J 6 9; J
乾癬指標遺伝子が i)または iii)に記載された遺伝子である場合、 乾癬指標遺伝 子の発現の上昇は、 その症状の原因が乾癬である可能性が高いことを示してい る。 また、 乾癬が疑われる症状を示す患者において、 乾癬指標遺伝子が ii)また は iv)に記載された遺伝子である場合、 乾癬指標遺伝子の発現の低下は、 その症 状の原因が同じく乾癬である可能性が高いことを示している。 When the psoriasis indicator gene is a gene described in i) or iii), an increased expression of the psoriasis indicator gene indicates that the cause of the symptom is likely to be psoriasis. If the psoriatic index gene is a gene described in ii) or iv) in a patient who exhibits symptoms suspected of psoriasis, a decrease in the expression of the psoriasis index gene is also caused by psoriasis. It indicates that the possibility is high.
あるいは、 乾癬が改善に向かっているのかどうかを判断するための検査が可 能となる。 つまり、 乾癬に対する治療効果の判定に有用である。 また、 乾癬と 診断された患者において、 乾癬指標遺伝子が i)または iii)に記載された遺伝子 である場合、 乾癬指標遺伝子の発現の上昇は、 乾癬がさらに進行している可能 性が高いことを示している。 また、 乾癬と診断された患者において、 乾癬指標 遺伝子が ii)または iv)に記載された遺伝子である場合、 乾癬指標遺伝子の発現 の低下は、 同じく乾癬がさらに進行している可能性が高いことを示している。 更に、 発現レベルの違いに基づいて乾癬の重症度を判定することもできる。 すなわち、 乾癬指標遺伝子が i)または iii)に記載された遺伝子である場合、 乾 癬指標遺伝子の発現の上昇の程度は、 乾癬の重症度に相関する。 あるいは乾癬 指標遺伝子が ii)または iv)に記載された遺伝子である場合、 乾癬指標遺伝子の 発現の低下の程度が、 乾癬の重症度に相関する。  Alternatively, tests can be done to determine whether psoriasis is improving. In other words, it is useful for determining the therapeutic effect on psoriasis. In patients diagnosed with psoriasis, when the psoriasis indicator gene is a gene described in i) or iii), an increase in the expression of the psoriasis indicator gene indicates that psoriasis is more likely to have progressed further. Is shown. In patients diagnosed with psoriasis, if the psoriasis indicator gene is the gene described in ii) or iv), a decrease in the expression of the psoriasis indicator gene indicates that psoriasis is more likely to progress further. Is shown. In addition, the severity of psoriasis can be determined based on differences in expression levels. That is, when the psoriasis indicator gene is a gene described in i) or iii), the degree of increase in the expression of the psoriasis indicator gene correlates with the severity of psoriasis. Alternatively, when the psoriasis indicator gene is a gene described in ii) or iv), the degree of decrease in the expression of the psoriasis indicator gene correlates with the severity of psoriasis.
また本発明は、 a)、 c)、 および c' )のいずれかに記載の AD指標遺伝子または AD指標遺伝子と機能的に同等な遺伝子の、 皮膚における発現強度を上昇させた トランスジエニック非ヒト動物からなるアトピー性皮膚炎モデル動物に関する。 本発明によって、 a)に記載の AD指標遺伝子の発現強度が、 アトピー性皮膚炎 患者の皮疹部において上昇することが明らかとなった。 同様に、 c)および c )に 記載の AD指標遺伝子の発現強度が、 アトピー性皮膚炎患者の無疹部において上 昇することが明らかとなった。 したがって、 皮膚において、 a)、 c)、 および c' ) のいずれかに記載の AD指標遺伝子または AD指標遺伝子と機能的に同等な遺伝 子の発現レベルを人為的に増強した動物は、 アトピー性皮膚炎のモデル動物と して利用することができる。 Further, the present invention provides a transgenic non-human having an increased expression intensity in the skin of the AD indicator gene or a gene functionally equivalent to the AD indicator gene according to any of a), c) and c ′). The present invention relates to an animal model of atopic dermatitis comprising an animal. According to the present invention, it has been clarified that the expression intensity of the AD indicator gene described in a) increases in the rash area of a patient with atopic dermatitis. Similarly, it was revealed that the expression intensity of the AD indicator gene described in c) and c) was increased in the rash-free area of patients with atopic dermatitis. Therefore, animals that artificially enhance the expression level of the AD indicator gene described in any of a), c ) and c ') or a gene functionally equivalent to the AD indicator gene in the skin are atopic With dermatitis model animals You can use it.
また本発明は、 b)、 d)、 および d' )のいずれかに記載の AD指標遺伝子または AD指標遺伝子と機能的に同等な遺伝子の、 皮膚における発現強度を低下させた トランスジヱニック非ヒト動物からなるアトピー性皮膚炎モデル動物に関する。 本発明によって、 b)に記載の AD指標遺伝子の発現強度が、 アトピー性皮膚炎 患者の皮疹部において低下することが明らかとなった。 同様に、 d)および d' )に 記載の AD指標遺伝子の発現強度が、 アトピー性皮膚炎患者の無疹部において低 下することが明らかとなった。 したがって、 皮膚において、 b)、 d)、 および d，） のいずれかに記載の AD指標遺伝子または AD指標遺伝子と機能的に同等な遺伝 子の発現レベルを人為的に低下させた動物は、 アトピー性皮膚炎のモデル動物 として利用することができる。  In addition, the present invention provides a transgenic non-drug which has reduced expression intensity in the skin of the AD indicator gene or a gene functionally equivalent to the AD indicator gene according to any of b), d) and d '). The present invention relates to an animal model of atopic dermatitis comprising a human animal. According to the present invention, it has been clarified that the expression intensity of the AD indicator gene described in b) is reduced in the rash area of a patient with atopic dermatitis. Similarly, it became clear that the expression intensity of the AD indicator gene described in d) and d ′) was reduced in the eruption of atopic dermatitis patients. Therefore, animals in which the expression level of the AD indicator gene described in any of b), d) and d, or the gene functionally equivalent to the AD indicator gene in the skin is artificially reduced, It can be used as a model animal for atopic dermatitis.
また本発明は、 i)または iii)に記載の乾癬指標遺伝子または乾癬指標遺伝子 と機能的に同等な遺伝子の、 皮膚における発現強度を上昇させたトランスジェ ニック非ヒト動物からなる乾癬モデル動物に関する。  The present invention also relates to a psoriasis model animal comprising a transgenic non-human animal having an increased expression level in the skin of the psoriasis indicator gene described in i) or iii) or a gene functionally equivalent to the psoriasis indicator gene.
本発明によって、 i)に記載の乾癬指標遺伝子の発現強度が、 乾癬患者の皮疹 部において上昇することが明らかとなった。 同様に、 iii)に記載の乾癬指標遺 伝子の発現強度が、 乾癬患者の無疹部において上昇することが明らかとなった。 したがって、 皮膚において、 i)または iii)に記載の乾癬指標遺伝子または乾癬 指標遺伝子と機能的に同等な遺伝子の発現レベルを人為的に増強した動物は、 乾癬のモデル動物として利用することができる。  According to the present invention, it has been clarified that the expression intensity of the psoriasis indicator gene described in i) increases in the rash of psoriatic patients. Similarly, it became clear that the expression intensity of the psoriasis indicator gene described in iii) was increased in the rash-free area of psoriatic patients. Therefore, an animal in which the expression level of the psoriasis indicator gene described in i) or iii) or a gene functionally equivalent to the psoriasis indicator gene in the skin is artificially enhanced can be used as a psoriasis model animal.
また本発明は、 ii)または iv)に記載の乾癬指標遺伝子または乾癬指標遺伝子 と機能的に同等な遺伝子の、 皮膚における発現強度を低下させたトランスジェ ニック非ヒト動物からなる乾癬モデル動物に関する。  The present invention also relates to a psoriasis model animal comprising a transgenic non-human animal having a reduced expression level in the skin of the psoriasis indicator gene described in ii) or iv) or a gene functionally equivalent to the psoriasis indicator gene.
本発明によって、 ii)に記載の乾癬指標遺伝子の発現強度が、 乾癬患者の皮疹 部において低下することが明らかとなった。 同様に、 iv)に記載の乾癬指標遺伝 子の発現強度が、 乾癬患者の無疹部において低下することが明らかとなった。 したがって、 皮膚において、 ii)または iv)に記載の乾癬指標遺伝子または乾癬 指標遺伝子と機能的に同等な遺伝子の発現レベルを人為的に低下させた動物は、 乾癬のモデル動物として利用することができる。 According to the present invention, it has been clarified that the expression intensity of the psoriasis indicator gene described in ii) is reduced in the rash of psoriatic patients. Similarly, it was revealed that the expression intensity of the psoriasis indicator gene described in iv) was reduced in the rash-free area of psoriatic patients. Therefore, an animal in which the expression level of the psoriasis indicator gene described in ii) or iv) or a gene functionally equivalent to the psoriasis indicator gene in the skin is artificially reduced can be used as a model animal for psoriasis. .
本発明において機能的に同等な遺伝子とは、 指標遺伝子によってコードされ る蛋白質において明らかにされている活性と同様の活性を備えた蛋白質をコー ドする遺伝子である。 機能的に同等な遺伝子の代表的なものとしては、 被験動 物が本来備えている、 その動物種における指標遺伝子のカウンターパートを挙 げることができる。 たとえば前記 A)群 - D〉群に記載の遺伝子は、 マウスにおける 機能的に同等な遺伝子である。 A)群- D)群に記載された遺伝子は、 本発明に基づ くスクリ一二ングをマウスを用いて実施するときに望ましい指標遺伝子である。 更に本発明は、 a)- d)に記載の AD指標遺伝子のマウスにおけるカウンターパ 一トを明らカにした。 a) - d)に記載の指標遺伝子に対するマウス力ゥンターパ一 トは、 それぞれ A) -D)として記載した。 これらのカウンターパートは、 感作マウ ス耳介皮膚と非感作マゥス耳介皮膚における遺伝子の発現レベルを比較したと きに、 2倍以上の差が見られた遺伝子である。  In the present invention, a functionally equivalent gene is a gene that encodes a protein having the same activity as that clarified in the protein encoded by the indicator gene. Representative examples of functionally equivalent genes include the counterpart of the indicator gene in the animal species that the test animal originally has. For example, the genes described in the groups A) to D> are functionally equivalent genes in mice. A) Group-The genes described in Group D) are desirable indicator genes when screening according to the present invention is performed using mice. Furthermore, the present invention has clarified the counterpart in mice of the AD indicator gene described in a) to d). The mouse interaction percentages for the indicator genes described in a) to d) are described as A) to D), respectively. These counterparts are genes that showed a two-fold or more difference when comparing gene expression levels in sensitized mouse auricle skin and non-sensitized mouse auricle skin.
したがって、 これらのカウンタ一パートの発現レベルの調節や、 投与によつ て、 アトピー性皮膚炎モデル動物を作り出すことができる。 すなわち本発明は、 A) - D)に記載の遺伝子群の発現レベルの調節による、 アトピー性皮膚炎モデル動 物の製造方法に関する。 あるいは本努明は、 A) -D)に記載の遺伝子群によってコ ードされるタンパク質その の、 または該タンパク質の抗体を非ヒト動物に投 与する工程を含む、 ァトピー性皮膚炎モデル動物の製造方法に関する。  Therefore, an atopic dermatitis model animal can be created by adjusting the expression level of these counterparts or by administering them. That is, the present invention relates to a method for producing an atopic dermatitis model animal by regulating the expression levels of the genes described in A) to D). Alternatively, the present effort is directed to a method of producing an animal model of atopic dermatitis, which comprises a step of administering a protein encoded by the genes described in A) to D) or an antibody of the protein to a non-human animal. It relates to a manufacturing method.
まず、 A)または C)に記載された遺伝子群は、 a)、 、 および c' )のいずれか に記載の遺伝子群と同様に、 発現レベルの上昇によってアトピー性皮膚炎を誘 導することができる。 あるいはこれらの遺伝子群から選択された遺伝子や、 そ の遺伝子がコードするタンパク質の投与によって、 アトピー性皮膚炎モデル動 物を作り出すことができる。 これらのカウンターパートはいずれもマウスの遺 伝子であることから、 遺伝子やタンパク質を投与する場合には、 マウスに投与 するのが望ましい。 First, the genes described in A) or C), like the genes described in any of a) ,, and c '), can induce atopic dermatitis by increasing their expression levels. it can. Alternatively, an atopic dermatitis model animal can be created by administering a gene selected from these gene groups or a protein encoded by the gene. All of these counterparts are the remains of mice. Because it is a gene, it is desirable to administer genes and proteins to mice when administering them.
また、 B)または D)に記載された遺伝子群は、 b)、 d)、 および d' )のいずれか に記載の遺伝子群と同様に、 発現レベルの抑制によって、 アトピー性皮膚炎を 誘導することができる。 あるいはこれらの遺伝子群から選択された遺伝子の発 現や、 その遺伝子がコードするタンパク質の活性を抑制することによって、 ァ トビー性皮膚炎を作り出すことができる。 発現の抑制には、 アンチセンス核酸、 あるいは RNAi を利用することができる。 タンパク質の活性の調節には、 抗体な どの活性阻害物質の投与が有効である。 すなわち、 B)または D)に記載の遺伝子 群を先天的に有する動物、 すなわちマウスに、 これらの成分を投与することに よってアトピー性皮膚炎が誘導される。  In addition, the gene group described in B) or D) induces atopic dermatitis by suppressing the expression level, like the gene group described in any of b), d) and d '). be able to. Alternatively, atby dermatitis can be created by suppressing the expression of a gene selected from these genes and the activity of the protein encoded by the gene. Antisense nucleic acid or RNAi can be used to suppress expression. Administration of an activity inhibitor such as an antibody is effective for regulating the activity of a protein. That is, atopic dermatitis is induced by administering these components to an animal, ie, a mouse, having the gene group described in B) or D) innately.
該ァトピー性皮膚炎モデル動物は、 ァトピー性皮膚炎における生体内の変化 を明らかにするために有用である。 更に、 該アトピー性皮膚炎モデル動物を使 用することにより、 指標遺伝子のさらなる機能を解明すること、 およぴ該遺伝 子を標的とする薬剤を評価することには大きな意義がある。  The atopic dermatitis model animal is useful for elucidating in vivo changes in atopic dermatitis. Furthermore, using the atopic dermatitis model animal to elucidate the further function of the indicator gene and evaluating a drug targeting the gene are of great significance.
また本突明によるアトピー性皮膚炎モデル動物は、 アトピー性皮膚炎のメカ ュズムの解明、 さらにはスクリーニングされた化合物の安全性の試験に有用で ある。 たとえば本発明によるアトピー性皮膚炎モデル動物が皮膚炎を発症した り、 何らかのアレルギー性疾患に関連した測定値の変化を示せば、 それを回復 させる作用を持つた化合物を探索するスクリーニングシステムが構築できる。 本発明において、 発現レベルの上昇とは、 指標遺伝子が外来遺伝子として導 入され強制発現している状態、 あるいは被験動物が本来備えている指標遺伝子 の転写と蛋白質への翻訳が増強されている状態、 並びに翻訳産物である蛋白質 の分解が抑制された状態のいずれかを意味する。  In addition, the atopic dermatitis model animal according to the present invention is useful for elucidating the mechanism of atopic dermatitis and for testing the safety of screened compounds. For example, if an animal model of atopic dermatitis according to the present invention develops dermatitis or shows a change in measured values related to any allergic disease, a screening system for searching for a compound having an action to restore it can be constructed. . In the present invention, an increase in the expression level refers to a state in which the indicator gene is introduced as a foreign gene and is forcibly expressed, or a state in which the transcription and translation of the indicator gene originally provided in the test animal are enhanced. And any state in which the degradation of the protein as a translation product is suppressed.
本発明において、 発現レベルの低下とは、 被験動物が備える指標遺伝子の転 写と蛋白質への翻訳が阻害されている状態、 あるいは翻訳産物である蛋白質の 分解が促進された状態のいずれかを意味する。 遺伝子の発現レベルは、 たとえ ば実施例に示すような DNAチップにおけるシグナル強度の差により確認するこ とができる。 また翻訳産物である蛋白質の活性は、 正常な状態と比較すること により確認することができる。 In the present invention, a decrease in the expression level refers to a state in which the transcription of the indicator gene provided in the test animal and the translation into the protein are inhibited, or the expression of the protein as a translation product. Means any of the states where decomposition is promoted. The gene expression level can be confirmed, for example, by a difference in signal intensity on a DNA chip as shown in Examples. The activity of the protein as a translation product can be confirmed by comparison with a normal state.
代表的なトランスジェニック動物は、 指標遺伝子を導入し強制発現させた動 物、 または指標遺伝子をノックアウトした動物、 他の遺伝子と置換 （ノックィ ン） した動物等を示すことができる。 また、 指標遺伝子に対するアンチセンス D NA、 リボザィムをコードする DNA、 あるいはデコイ核酸として機能する DNA等を 導入したトランスジヱニック動物も、 本発明におけるトランスジェユック動物 として用いることができる。 その他、 たとえば指標遺伝子のコード領域に変異 を導入し、 その活4を増強あるいは抑制したり、 あるいは分解されにくいある 、は分解されやすいァミノ酸配列に改変した動物などを示すことができる。 ァ ミノ酸配列の変異として、 置換、 欠失、 挿入、 あるいは付加を示すことができ る。 その他、 遺伝子の転写調節領域を変異させることにより、 本発明の指標遺 伝子の発現そのものを調節することもできる。  Representative transgenic animals include animals into which the indicator gene has been introduced and forced to be expressed, animals in which the indicator gene has been knocked out, and animals in which the gene has been replaced (knock-in) with other genes. In addition, transgenic animals into which antisense DNA against the indicator gene, DNA encoding ribozyme, DNA functioning as a decoy nucleic acid, or the like has been introduced can also be used as the transgenic animal in the present invention. In addition, for example, an animal in which a mutation is introduced into the coding region of the indicator gene to enhance or suppress its activity 4 or is hardly degraded, or an animal modified to a degradable amino acid sequence can be shown. Mutations in the amino acid sequence can include substitutions, deletions, insertions, or additions. In addition, by mutating the transcriptional regulatory region of the gene, the expression itself of the indicator gene of the present invention can also be regulated.
特定の遺伝子を対象として、 トランスジエニック動物を得る方法は公知であ る。 すなわち、 遺伝子と卵を混合してリン酸カルシウムで処理する方法や、 位 相差顕微鏡下で前核期卵の核に、 微小ピぺットで遺伝子を直接導入する方法 (マイクロインジェクション法、 米国特許第 4873191 号）、 胚性幹細胞 （ES細 胞） を使用する方法などによってトランスジエニック動物を得ることができる。 その他、 レトロウイルスベクターに遺伝子を挿入し、 卵に感染させる方法、 ま た、 精子を介して遺伝子を卵に導入する精子ベクター法等も開発されている。 精子ベクター法とは、 精子に外来遺伝子を付着またはエレクトロポレーシヨン 等の方法で精子細胞内に取り込ませた後に、 卵子に受精させることにより、 外 来遺伝子を導入する遺伝子組換え法である （M. Lavitranoet ら Cell， 57， 717， 1989)。 発現ベクターに使用するプロモーターとして、 適当な薬剤等の物質により転 写が調節されるプロモーターを用いれば、 該物質の投与によってトランスジェ 二ック動物における外来性の指標遺伝子の発現レベルを調整することができる。 本発明のアトピー性皮膚炎または乾癬のモデル動物として用いるトランスジ エニック動物は、 ヒト以外のあらゆる脊椎動物を利用して作成することができ る。 具体的には、 マウス、 ラット、 ゥサギ、 ミニブタ、 ャギ、 ヒッジ、 あるい はゥシ等の脊椎動物において様々な遺伝子の導入や発現レベルを改変されたト ランスジエニック動物が作り出されている。 Methods for obtaining transgenic animals by targeting specific genes are known. That is, a method in which a gene and an egg are mixed and treated with calcium phosphate, or a method in which a gene is directly introduced into a nucleus of a pronuclear stage egg under a phase contrast microscope with a minute pipe (microinjection method, US Pat. No. 4,873,191). Transgenic animals can be obtained by methods using embryonic stem cells (ES cells). In addition, a method of inserting a gene into a retroviral vector and infecting an egg, a method of introducing a gene into an egg via sperm, and a sperm vector method have also been developed. The sperm vector method is a genetic recombination method in which a foreign gene is attached to sperm or incorporated into sperm cells by a method such as electroporation, and then fertilized by an egg to introduce the foreign gene. M. Lavitranoet et al. Cell, 57, 717, 1989). When a promoter whose transcription is regulated by a substance such as an appropriate drug is used as the promoter used in the expression vector, the expression level of the exogenous indicator gene in the transgenic animal can be adjusted by administering the substance. Can be. The transgenic animal used as a model animal for atopic dermatitis or psoriasis of the present invention can be prepared using any vertebrate other than human. Specifically, transgenic animals in which various genes have been introduced or their expression levels have been altered in vertebrates such as mice, rats, porch egrets, miniature pigs, goats, sheep, and porch have been created. .
さらに本発明は、 ァトピー性皮膚炎治療薬候補化合物のスクリ一二ング方法 に関する。 本発明において、 AD指標遺伝子は a：)〜 d)、 並びに c' )および d' )の いずれかに記載の群から選択された遺伝子である。 a)に記載の群から選択され た遺伝子は、 アトピー性皮膚炎患者の無疹部に比較して同一の患者の皮疹部に おいて有意に発現レベルが上昇している。 b)に記載の群から選択された遺伝子 は、 アトピー性皮膚炎患者の無疹部に比較して同一の患者の皮疹部において有 意に発現レベルが低下している。 c)ならびに c' )に記載の群から選択された遺伝 子は、 健常者と比較してアトピー性皮膚炎患者の無疹部において有意に発現レ ベルが上昇している。 そして d)ならびに d' )に記載の群から選択された遺伝子 は、 健常者と比較してアトピー性皮膚炎患者の無瘆部において有意に発現レべ ルが低下している。  Furthermore, the present invention relates to a method for screening a candidate compound for treating atopic dermatitis. In the present invention, the AD indicator gene is a gene selected from the group described in any of a :) to d), and c ′) and d ′). The expression level of the gene selected from the group described in a) is significantly increased in the eruption area of the same patient as that of the non-eruption area of the atopic dermatitis patient. The expression level of the gene selected from the group described in b) is significantly lower in the rash area of the same patient than in the rash area of the atopic dermatitis patient. Genes selected from the groups described in c) and c ') have significantly increased expression levels in the eruptions of atopic dermatitis patients as compared to healthy subjects. The expression levels of the genes selected from the groups described in d) and d ′) are significantly lower in the atopic part of atopic dermatitis patients than in healthy persons.
したがって、 a)群、 c〉群 るいは c' )群の AD指標遺伝子については、 前記 AD 指標遺伝子の発現レベルを低下させることができる化合物を選択することによ つて、 アトピー性皮膚炎の治療薬を得ることができる。 一方 b)群、 d)群あるい は d' )群の AD指標遺伝子については、 前記 AD指標遺伝子の発現レベルを上昇さ せることができる化合物を選択することによって、 アトピー性皮膚炎の治療薬 を得ることができる。  Therefore, for the AD indicator genes in the groups a), c> and c ′), treatment of atopic dermatitis can be performed by selecting a compound capable of reducing the expression level of the AD indicator genes. You can get medicine. On the other hand, as for the AD indicator gene of the group b), d) or d '), by selecting a compound capable of increasing the expression level of the AD indicator gene, a therapeutic agent for atopic dermatitis is selected. Can be obtained.
本発明によるアトピー性皮膚炎治療薬候補化合物のスタリー二ング方法にお いて、 AD指標遺伝子として好ましい遺伝子として以下に記載の遺伝子を示すこ とができる。 The method of staring candidate compounds for the treatment of atopic dermatitis according to the present invention In addition, the following genes can be shown as preferred genes for the AD indicator gene.
a)群の遺伝子として好ましい遺伝子： metalloproteinase (匿）、 type IV coll agenase^ cathepsin Z precursor (CTSZ)ヽ disintegrin-proteaseヽ pro- cathep sin L (major excreted protein MEP)、 skin collagenases SPUVE (protease, serine, 23)、 Proprotein convertase subtilisin/kexin typel、 tissue inhib itor of metalloproteinasesN beta-migrating plasminogen activator in ibi tor I、 IL- 13Ral、 IFN-beta 2a (IL- 6)、 heparin- binding EGF-like growth fa ctor、 GM-CSFR beta、 interleukin 8 (IL8)、 MCP - 1、 EBIl-ligand chemokine、 SLCN GRO - beta、 monocyte chemotactic protein-2、 CCR1、 lymph node homing receptor / L - selectin、 endothelial leukocyte adhesion molecule 1 (ELAM - 1)、 leukocyte adhesion protein (LFA - 1/Mac - l/pl50, 95 family) betaN TNFAI Po (tumor necrosis factor, alpha-induced protein 6)、 M130 antigen extra cellular variant / CD163、 CD53 glycoprotein^ T200 leukocyte common anti gen (CD45, LC-A) isoforra 1-3、 THY - 1 (CD90)、 leucocyte i腿 unoglobulin - li ke receptor - 3 (LIR- 3) tenascin - Cゝ alpha - 1 type XV collagenヽ cartilage o丄 igomeric matrix protein (C0MP)、 proteoglycan 1、 immunoglobulin lambda light chainヽ Fc - epsi Ion -; receptor ga讓 a - chain、 IgG low affinity Fc frag ment receptor (CD32) immunoglobulin heavy constant gamma 3 (G3m marke r) N immunoglobulin kappa constant^ hemopoietic ceil protein— tyrosine ki nase (HCK)、 KIAA0687 / MAP4K4、 ornithine decarboxylase ODC (EC 4. 1. 1. 1 7)ヽ phospholipase A2, group IIA (platelets, synovial fluid)、 nicotinami de N-methyltransf erase ( NMT)、 actin related protein 2/3 complex, subun it IB (41 kD)、 myosin IBヽ ga腿 a - interferon - inducible protein (IP - 30)、 R AB31、 regulator of G- protein signalling 1 (BL34)、 TNRC3、 insulin-like gr owth factor binding protein 4 (IGFBP4)、 nel - related protein 2、 neuronal tissue-enriched acidic protein (NAP - 22)ヽ DKFZp58600118 / KI 1199、 lys osomal-associated multitransmembrane protein (LAPTm5)、 KI 0296、 serum amyloid Λ丄、 TYRO protein tyrosine kinase binding proteins fatty acid bi nding protein omologue (PA- FABP)ヽ fibrinogen- like 2ゝ およぴ six transme mbrane epithelial antigen of the prostate (STEAP) a) Genes preferred as group genes: metalloproteinase (secret), type IV coll agenase ^ cathepsin Z precursor (CTSZ) Z disintegrin-protease ヽ pro-cathepsin L (major excreted protein MEP), skin collagenase s SPUVE (protease, serine) , 23), Proprotein convertase subtilisin / kexin typel, tissue inhib itor of metalloproteinases N beta-migrating plasminogen activator in ibi tor I, IL-13Ral, IFN-beta 2a (IL-6), heparin-binding EGF-like growth factor , GM-CSFR beta, interleukin 8 (IL8), MCP-1, EBIl-ligand chemokine, SLC N GRO-beta, monocyte chemotactic protein-2, CCR1, lymph node homing receptor / L-selectin, endothelial leukocyte adhesion molecule 1 ( ELAM-1), leukocyte adhesion protein (LFA-1 / Mac-l / pl50, 95 family) beta N TNFAI Po (tumor necrosis factor, alpha-induced protein 6), M130 antigen extra cellular variant / CD163, CD53 glycoprotein ^ T200 leukocyte common anti gen (CD45, LC-A) isoforra 1-3, THY-1 (CD90), leucocy te i thigh unoglobulin-liquid receptor-3 (LIR-3) tenascin-C ゝ alpha-1 type XV collagen ヽ cartilage o 丄 igomeric matrix protein (C0MP), proteoglycan 1, immunoglobulin lambda light chain ヽ Fc-epsi Ion-; receptor ga Source a-chain, IgG low affinity Fc fragment receptor (CD32) immunoglobulin heavy constant gamma 3 (G3m marker) N immunoglobulin kappa constant ^ hemopoietic ceil protein— tyrosine kinase (HCK), KIAA0687 / MAP4K4, ornithine decarboxylase ODC (EC 4.1.1.17) ヽ phospholipase A2, group IIA (platelets, synovial fluid), nicotinami de N-methyltransf erase (NMT), actin related protein 2/3 complex, subun it IB (41 kD), myosin IB ヽ ga thigh a-interferon-inducible protein (IP-30), R AB31, regulator of G-protein signaling 1 (BL34), TNRC3, insulin-like growth factor binding protein 4 (IGFBP4), nel-related protein 2, neuronal tissue-enriched acidic protein (NAP-22) ヽ DKFZp58600118 / KI 1199, lys osomal-associated multitransmembrane protein (LAPTm5), KI 0296, serum amyloid Λ 丄, TYRO protein tyrosine kinase binding protein s fatty acid binding protein omologue (PA- FABP) ヽ fibrinogen- like 2 ゝ and six transme mbrane epithelial antigen of the prostate (STEAP)
b)群の遺伝子として好ましい遺伝子： cathepsin V、 SERPINB7 (serine or cys teine) proteinase inhibitor, claae B ^ovalbumin)， member 7)、 cvtokerati n 15、 desmin、 extracellular matrix protein 2、 KIAA0537、 deoxyribonuclea se I - like 2 (DNAS1L2) s phosphoenolpyruvate carboxykinase (PCK1)、 3-hydr oxy-3-methylglutaryl coenzyme A synthases arylacetamide deacetylase、 AT Pase, Cu++ transporting, alpha polypeptide (ATP7A)ゝ yrosinase (TYR)ヽ m onoamine oxidase A、 Aldehyde dehydrogenase 5 family, member Al、 alcohol dehydrogenase 1A (class I) , alpha polypeptide^ alcohol dehydrogenase 1 C (class I) , gamma polypeptideゝ degenerative spermatocyte homo log (sphi ngolipid delta 4 de saturate)ゝ alpha - 2 - glycoprotein 1， zincヽ perilipin、 lipoprotein lipaseヽ aldehyde dehydrogenase 3 family, member A2ヽ Hemoglo bin alpha 1， alpha 2 chain、 class I homeoprotein (H0XA9)、 promyelocytic leukemia zinc finger protein (PLZF)ゝ calcium channel, voltage - dependen t, alpha 1H subunit、 sodium channel, nonvoltage-gated 1， beta、 LIG1 (or tholog of mouse integral membrane glycoprotein UG - 1)、 WFSl (Wolfram sy n drome 1)、 rogesterone receptor membrane component 2、 peanut-like 1 (D rosophila)、 type 1 angiotensin II receptor, variant 1-5、 EphB6、 betacel lulin、 proline rich 4 (lacrimal)、 retinol binding protein 4、 DKFZP434G0 310 (hypothetical protein) , loricrin、 DKFZp586H2123, KIAA0624, DKFZp564 D206、 DKFZp586F1223 b) Genes preferred as group genes: cathepsin V, SERPINB7 (serine or cys teine) proteinase inhibitor, claae B ^ ovalbumin), member 7), cvtokeratin 15, desmin, extracellular matrix protein 2, KIAA0537, deoxyribonuclea se I-like 2 (DNAS1L2) s phosphoenolpyruvate carboxykinase (PCK1), 3-hydroxy-3-methylglutaryl coenzyme A synthase s arylacetamide deacetylase, AT Pase, Cu ++ transporting, alpha polypeptide (ATP7A) ゝ yrosinase (TYR) ヽ monoamine oxidase A, Aldehyde dehydrogenase 5 family, member Al, alcohol dehydrogenase 1A (class I), alpha polypeptide ^ alcohol dehydrogenase 1 C (class I), gamma polypeptide ゝ degenerative spermatocyte homo log (sphi ngolipid delta 4 de saturate) ゝ alpha-2-glycoprotein 1, zincヽ perilipin, lipoprotein lipase ヽ aldehyde dehydrogenase 3 family, member A2 ヽ Hemoglo bin alpha 1, alpha 2 chain, class I homeoprotein (H0XA9), promyelocytic leukemia zinc finger protein (PLZF) ゝ calcium channel, voltage- dependen t, alpha 1H subunit, sodium channel, nonvoltage-gated 1, beta, LIG1 (or tholog of mouse integral membrane glycoprotein UG-1), WFSl (Wolfram sy n drome 1), rogesterone receptor membrane component 2, peanut-like 1 (D rosophila), type 1 angiotensin II receptor, variant 1-5, EphB6, betacel lulin, proline rich 4 (lacrimal), retinol binding protein 4, DKFZP434G0 310 (hypothetical protein), loricrin, DKFZp586H2123, KIAA0624, DKFZp564DpF206K
c，）群の遺伝子として好ましい遺伝子： BTF3 protein homologue, general tran scription factor I IF, polypeptide 2, 30kDa、 alternative activated macro phage specific CC chemokine 1、 complement component 1, q subcomponent, beta polypeptides transforming growth factor, beta receptor III (betagl yean, 300kD)、 branched chain alpha-ketoacid dehydrogenase kinase^ ATPas e, Ca++ transporting, ubiquitous^ tyrosinase - related protein 1 histidi ne ammonia— lyase、 androgen - regulate d short-chain dehydrogenase/reductas e 1、 gap junction protein, beta 3, 31kD (connexin 31)、 KI 0440、 lympho id-restricted membrane protein (LRMP) S raatrilysin (MMP7)、 specific gran ule protein (28 kDa) (SGP28) type I sigma receptor % FK506 binding prot ein IB, 12. 6 kDa、 Prolactin - Induced Protein^ SET binding factor 1 (SBF 1)、 および FLJ12525 Preferred genes for c,) group: BTF3 protein homologue, general tran scription factor I IF, polypeptide 2, 30kDa, alternative activated macro phage specific CC chemokine 1, complement component 1, q subcomponent, beta polypeptides transforming growth factor, beta receptor III (betagl yean, 300kD), branched chain alpha-ketoacid dehydrogenase kinase ^ ATPas e, Ca ++ transporting, ubiquitous ^ tyrosinase-related protein 1 histidi ne ammonia- lyase, androgen-regulate d short-chain dehydrogenase / reductas e 1, gap junction protein, beta 3, 31kD (connexin 31), KI 0440, lympho id -restricted membrane protein (LRMP) S raatrilysin (MMP7), specific granule protein (28 kDa) (SGP28) type I sigma receptor % FK506 binding protein IB, 12.6 kDa, Prolactin-Induced Protein ^ SET binding factor 1 ( SBF 1), and FLJ12525
d，）群の遺伝子として好ましい遺伝子： Idl、 BTG2、 zinc finger protein 36， C 3H type-like 1、 EGRl (early growth response 1)、 MIP - 1 - alpha、 MCP1、 turao r necrosis factor receptor superfamily, member 13B、 HB15 / CD83、 CD95, F AS、 CD69、 T cell receptor delta locusN caspase 3, apoptosis - related cys teine protease^ serine (or cysteine) proteinase inhibitor, clade I (neu roserpin) , member 1、 SERPINE1、 prostaglandin D2 synthase 21kDa (brain)、 cholesterol 25— hydroxylase、 glutathione S— transferase M3 (brain)、 prote in phosphatase 5, catalytic subunit phosphodiesterase 3B、 regulator of G— protein signalling 16、 hepar in-binding EGF - like growth factor^ pleio rophin、 weel tyrosine kinase^ SMARCD3、 IgG Fc binding protein^ chorion ic gonadotropin beta subunit、 keratin, hair, acidic, 3A、 37 kDa leucin e-rich repeat (LRR) protein、 brain abundant, membrane attached signal p rotein 1、 SEC24 related gene family, member D (S. cerevisiae)、 Friedrei ch ataxia^ zinc finger protein 187、 zinc finger protein 337、 MLLT10% co llagen, type XIV， alpha 1 (undulin)、 molybdenum cofactor synthesis 3、 g uanylate binding protein 1， interferon-inducible, 67kDa、 ras homolog gen e family, member E、 armadillo repeat protein ALEX2、 keratin, hair, acid ic, 1、 YDD19 protein、 chromosome condensation 1、 dermatopontin^ P311 pr otein、 syntaxin 11、 M)RG family member 4、 rearranged L-myc fusion seque nce、 clone 24790、 IAA1095 protein, FLJ12280、 ESTs (Accession No. AC0049 40)、 および ESTs (Accession No. AI829701) Preferred genes for d,) group genes: Idl, BTG2, zinc finger protein 36, C3H type-like 1, EGRl (early growth response 1), MIP-1-alpha, MCP1, turao rnecrosis factor receptor superfamily, member 13B, HB15 / CD83, CD95, FAS, CD69, T cell receptor delta locus N caspase 3, apoptosis-related cys teine protease ^ serine (or cysteine) proteinase inhibitor, clade I (neu roserpin), member 1, SERPINE1, prostaglandin D2 synthase 21kDa (brain), cholesterol 25-hydroxylase, glutathione S-transferase M3 (brain), prote in phosphatase 5, catalytic subunit phosphodiesterase 3B, regulator of G-protein signaling 16, hepar in-binding EGF-like growth factor ^ pleio rophin, weel tyrosine kinase ^ SMARCD3, IgG Fc binding protein ^ chorion ic gonadotropin beta subunit, keratin, hair, acidic, 3A, 37 kDa leucin e-rich repeat (LRR) protein, brain abundant, membrane attached signal p rotein 1, SEC24 related gene family, member D (S. cerevisiae), Friedrei ch ataxia ^ zinc finger protein 187, zinc finger protein 337, MLLT10 % collagen, type XIV, alpha 1 (undulin), molybdenum cofactor synthesis 3, g uanylate binding protein 1, interferon-inducible, 67kDa, ras homolog gene family, member E, armadillo repeat protein ALEX2, keratin, hair, acid ic, 1, YDD19 protein, chromosome condensation 1, dermatopontin ^ P311 pr otein, syntaxin 11, M) RG family member 4, rearranged L-myc fusion sequence, clone 24790, IAA1095 protein, FLJ12280, ESTs (Accession No.AC0049 40), and ESTs (Accession No.AI829701)
これらの遺伝子はいずれも、 乾癬患者では発現レベルの変化が見られなかつ た遺伝子である。 つまりアトピー性皮膚炎患者において特異的に発現レベルが 変化していた遺伝子と言うことができる。 これらの AD指標遺伝子の利用によつ て、 アトピー性皮膚炎症状に特異的な治療効果を評価することができる。  All of these genes have not been altered in psoriatic patients. In other words, it can be said that the gene whose expression level has been specifically changed in atopic dermatitis patients. By using these AD indicator genes, it is possible to evaluate the therapeutic effect specific to atopic dermatitis symptoms.
さらに本発明は、 乾癬治療薬候補化合物のスクリーニング方法に関する。 本 発明において、 乾癬指標遺伝子は i)〜iv)のいずれかに記載の群から選択された 遺伝子である。 i)に記載の群から選択された遺伝子は、 乾癬患者の無疹部に比 較して同一の患者の皮疹部において有意に発現レベルが上昇している。 ii)に記 載の群から選択された遺伝子は、 乾癬患者の無疹部に比較して同一の患者の皮 疹部において有意に発現レベルが低下している。 ii i)に記載の群から選択され 'た遺伝子は、 健常者と比較して乾癬患者の無疹部において有意に発現レベルが 上昇している。 そして iv)に記載の群から選択された遺伝子は、 健常者と比較し て乾癬患者の無疹部において有意に発現レベルが低下している。  Furthermore, the present invention relates to a method for screening a candidate compound for a therapeutic agent for psoriasis. In the present invention, the psoriasis indicator gene is a gene selected from the group described in any of i) to iv). The expression level of the gene selected from the group described in i) is significantly increased in the rash of the same patient as compared to the non-rash of the psoriasis patient. The gene selected from the group described in ii) has a significantly lower expression level in the rash area of the same patient compared to the non-rash area of the psoriatic patient. ii The gene selected from the group described in i) has a significantly increased expression level in the eruption area of psoriatic patients as compared to healthy persons. And the expression level of the gene selected from the group described in iv) is significantly lower in the eruption-free part of psoriatic patients than in healthy persons.
したがって、 i)群あるい iii)群の乾癬指標遺伝子については、 前記乾癬指 標遺伝子の発現レベルを低下させることができる化合物を選択することによつ て、 乾癬の治療薬を得ることができる。 一方 ii)群あるいは iv)群の乾癬指標遺 伝子については、 前記乾癬指標遺伝子の発現レベルを上昇させることができる 化合物を選択することによって、 乾癬の治療薬を得ることができる。  Therefore, for the psoriasis indicator gene of the group i) or iii), a therapeutic agent for psoriasis can be obtained by selecting a compound capable of reducing the expression level of the psoriasis indicator gene. . On the other hand, for the psoriatic index gene of the group ii) or iv), a therapeutic agent for psoriasis can be obtained by selecting a compound capable of increasing the expression level of the psoriatic index gene.
本発明による乾癬治療薬候補化合物のスクリーニング方法において、 乾癬指 標遺伝子として好ましい遺伝子として以下に記載の遺伝子を示すことができる。 i)群の遺伝子として好ましい遺伝子： cellular retinoic acid binding protei n 2、 proteasome (prosome, macropain) activator subunit 2、 interferon in duced 6-1 b protein^ heat shock 70kDa protein 4、 flap structure-specific endonuclease 1、 NME1、 eye 1 in-dependent kinase inhibitor 3、 ubiquitin-c onjugating enzyme E2C、 calreticulinN CDC2 geneヽ 画、 liver arginase (AR Gl)、 connexin 43 (GJAl, Cx43)、 interleukin 1 receptor antagonist^ ATP - b inding cassette, sub-family A (ABCl) , member 12、 M - phase phosphoproteinIn the method for screening a candidate compound for a therapeutic agent for psoriasis according to the present invention, the following genes can be shown as preferred genes as psoriatic indicator genes. i) Genes preferred as group genes: cellular retinoic acid binding protein 2, proteasome (prosome, macropain) activator subunit 2, interferon in duced 6-1 b protein ^ heat shock 70kDa protein 4, flap structure-specific endonuclease 1, NME1 , Eye 1 in-dependent kinase inhibitor 3, ubiquitin-conjugating enzyme E2C, calreticulin N CDC2 gene, liver arginase (AR Gl), connexin 43 (GJAl, Cx43), interleukin 1 receptor antagonist ^ ATP-binding cassette, sub-family A (ABCl), member 12, M-phase phosphoprotein
6、 creatine kinase, mitochondrial ·1、 Nedd4 binding protein 1、 solute c arrier family 7, member 5、 acid phosphatase, prostateN plakophilin 1、 U DP glycosyltransf erase 1 family, polypeptide A4、 ATPase, H+/K+ transpor ting, nongastric, alpha polypeptide^ cytoskeleton - associated protein 4、 glucosidase, beta; acid、 interferon - inducible 56 Kd prote inN low densit y lipoprotein receptor transglutaminase 3、 arachi donate 12-lipoxygenas e, 12R type、 CYP7B1、 tripartite motif-containing 14、 hypothetical prote in ]^」'21168、 heme oxygenase (decycling) 1、 S100 calcium binding protein6, creatine kinase, mitochondrial1, Nedd4 binding protein 1, solute carrier family 7, member 5, acid phosphatase, prostate N plakophilin 1, UDP glycosyltransf erase 1 family, polypeptide A4, ATPase, H + / K + transporting, nongastric , alpha polypeptide ^ cytoskeleton-associated protein 4, glucosidase, beta; acid, interferon-inducible 56 Kd prote in N low densit y lipoprotein receptor transglutaminase 3, arachi donate 12-lipoxygenas e, 12R type, CYP7B1, tripartite motif-containing 14, hypothetical prote in] ^ '' 21168, heme oxygenase (decycling) 1, S100 calcium binding protein
P、 gene from PAC 747L4、 SAM domain and HD domain 1、 arylsulfatase F、 p otassium inwardly - rectifying channel, subfamily J, member 15、 BUB1 budd ing uninniDited by benz imidazoles 1 homolog beta (yeast)、 SPllO nuclear body protein isoform b、 guanylate binding protein 1 (GBP1)、 GM2 gangli oside activator proteinN complement factor B preproprotein^ squalene ep oxidase^ solute carrier family 5 (sodium/glucose cotransporter) , memberP, gene from PAC 747L4, SAM domain and HD domain 1, arylsulfatase F, potassium inwardly-rectifying channel, subfamily J, member 15, BUB1 budding uninniDited by benz imidazoles 1 homolog beta (yeast), SPllO nuclear body protein isoform b , Guanylate binding protein 1 (GBP1), GM2 gangli oside activator protein N complement factor B preproprotein ^ squalene epoxidase ^ solute carrier family 5 (sodium / glucose cotransporter), member
1、 ZfflO interactor Zwint、 kallikrein 13、 interferon regulatory factor 7、 N-myc (and STAT) interactor % Stat2、 tripartite motif-containing 22、 kinesin - like 6、 kallikrein 10、 ribonucleotide reductase M2 polypeptide^ chromosome 1 open reading frame 29、 Sjogren syndrome antigen Al、 gamma - glutamyl hydrolase^ lymphocyte antigen 6 complex, locus E、 interleukin- 1 receptor antagonist^ interferon - induced protein 44、 lectin, galactosi de-binding, soluble, 3 binding protein^ retinoblastoma binding protein 6、 vipirin^ interferon-induced protein with tetratricopeptide repeats 4、 S100 calcium binding protein A12 (calgranulin C)、 bone marrow stromal c ell antigen 2、 chromosome 20 open reading frame 1、 aquaporin 3、 cystati n A (stefin A)、 KI 0186、 retinoblastoma - associated protein HEC、 NSl -as sociated protein 1、 topoisomerase (DNA) II alpha 170kDa、 H2A histone fa mily, member X、 chemokine · exodus— 1、 pituitary tumor - transforming 1、 SCO cytochrome oxidase deficient homo log 2 (yeast)、 CDC28 protein kinase r egulatory subunit 2、 kinesin - like 1、 histidine ammonia - lyase、 hypotheti cal protein FLJ10534、 cyclin El、 chromosome 1 open reading frame 34、 ce llular retinoic acid binding protein 2、 TTK protein kinaseヽ acid phosph atase, prostate^ interleukin 8 receptor beta (IL8RB) N RAB27A、 MX2、 thym idine Kinase 1、 interferon-inducible 56 Kd protein^ serum/glucocort i coi d regulated kinase^ EphA2、 nitric oxide synthase 2A、 plasminogen activa tor, tissue type、 GM2 ganglioside activator protein^ KIAA0963 protein kallikrein 13、 ATPase, Class V， type 10B、 よび GART 1, ZfflO interactor Zwint, kallikrein 13, interferon regulatory factor 7, N-myc (and STAT) interactor % Stat2, tripartite motif-containing 22, kinesin-like 6, kallikrein 10, ribonucleotide reductase M2 polypeptide ^ chromosome 1 open reading frame 29 , Sjogren syndrome antigen Al, gamma-glutamyl hydrolase ^ lymphocyte antigen 6 complex, locus E, interleukin- 1 receptor antagonist ^ interferon-induced protein 44, lectin, galactosi de-binding, soluble, 3 binding protein ^ retinoblastoma binding protein 6, vipirin ^ interferon-induced protein with tetratricopeptide repeats 4, S100 calcium binding protein A12 (calgranulin C), bone marrow stromal cell antigen 2, chromosome 20 open reading frame 1, aquaporin 3, cystatin A (stefin A), KI 0186, retinoblastoma-associated protein HEC, NSl -as sociated protein 1, topoisomerase (DNA) II alpha 170kDa, H2A histone fa mily, member X, chemokineexodus-1, pituitary tumor-transforming 1, SCO cytochrome oxidase deficient homo log 2 (yeast), CDC28 protein kinase r egulatory subunit 2, kinesin-like 1, histidine ammonia-lyase, hypotheti cal protein FLJ10534, cyclin El, chromosome 1 open reading frame 34, cellular retinoic acid binding protein 2, TTK protein kinase protein acid phosphatase, prostate ^ interleukin 8 receptor beta (IL8RB) N RAB27A, MX2, thymidine Kinase 1, interferon-inducible 56 Kd protein ^ serum / glucocort i coid regulated kinase ^ EphA2, nitric oxide synthase 2A, plasminogen activa tor, tissue type, GM2 ganglioside activator protein ^ KIAA0963 protein kallikrein 13, ATPase, Class V, type 10B and GART
ii)群の遺 ナとして好ましい遺 子： actin, alpha 2, smooth muscle, aorta、 actin, gamma 2, smooth muscle, entericN cisplatin resistance associated^ growth arrest-specific 6、 insulin -丄 ike growth factor binding protein 6 (IGFBP6)、 insulin induced protein 1 (INSIG1)、 PDGF receptor beta-like t umor suppressor (PRLTS)、 R-ras^ sarcospan (Kras oncogene - associated gen e)、 f ibroolast growth factor (FGF) receptor - 1、 fibronectin 1 isoform 1 preproprotein^ chromosome 21 open reading frame 25、 seven in absentia h omolog 1 (Drosophila)、 fatty acid desaturase 1、 fatty acid desaturase 2、 Rho— related BTB domain containing 3、 matrilin 2、 adipose specific 2、 LI 386 ii) Preferred genes for the group: actin, alpha 2, smooth muscle, aorta, actin, gamma 2, smooth muscle, enteric N cisplatin resistance associated ^ growth arrest-specific 6, insulin- 丄 ike growth factor binding protein 6 (IGFBP6), insulin induced protein 1 (INSIG1), PDGF receptor beta-like tumor suppressor (PRLTS), R-ras ^ sarcospan (Kras oncogene-associated gene), f ibroolast growth factor (FGF) receptor-1, fibronectin 1 isoform 1 preproprotein ^ chromosome 21 open reading frame 25, seven in absentia homolog 1 (Drosophila), fatty acid desaturase 1, fatty acid desaturase 2, Rho- related BTB domain containing 3, matrilin 2, adipose specific 2, LI 386
PCT/JP2003/009808  PCT / JP2003 / 009808
8 l | ； 8 l |;
M protein^ LIM domain binding 2 / CLIM1、 myosin l ight chain kinase (MLC K)、 myosin, light polypeptide 9, regulatory^ tropomyosin 1 (alpna cys teine-rich protein 1 (intestinal)、 reversion - inducing- cysteine -; rich pro tein with kazal motifs、 amine oxidase, copper containing 3 (vascular ad hesion protein 1)、 cytochrome c oxidase subunit Vila polypeptide 1 (mus cle)、 chemokine (C一 C motif) ligand 14、 ocular development-associated ge ne、 ephrin - B2、 Na，K - ATPase subunit alpha 2 (ATP1A2)、 ATPase, Ca++ trans porting, ubiquitous^ aquaporin 9、 pleiotrophinN cadherin 19， type 2、 WN T inhibitory factor 1、 WNTl inducible signaling pathway protein 2、 11— b eta - hydroxys tero id dehydrogenase (HSD11)、 myelin basic protein (MBP)ゝ p ro - galanin、 dihydropyrimidinase-like 3、 glypican- 4 (GPC4)、 acetylseroto nin 0™methyltransferase~like synuclein, ga醒 a、 connective tissue growt factor^ breast cancer anti-estrogen resistance 3、 heat shock 70kDa pr otein 2、 ets variant gene 1、 cAMP— dependent protein kinase subunit RII— beta、 microtubule - associated protein, RP/EB fami丄 y， member 2、 ATP - bindi ng cassette, sub-family C (CFTR/MRP) , member 3、 transmembrane 4 superfa mily member 2、 AXL receptor tyrosine kinase^ phospholatnbanゝ re fragment of IgG binding protein^ microsomal glutathione S - transferase 3、 DEPP (decidual protein induced by progesterone)、 Arg/Ab 1 - interact ing protein ArgBP2a (ArgBP2a)、 H0X2H mRNA from the Hox2 locus, ； frizzled- related pr otein、 G protein - coupled receptor, fami ly C， group 5， member B、 GABA— A receptor pi subimit、 mesenchyme homeo box 2 (growth arrest-specinc horn eo box)ヽ keratin 7、 tumor— associated calcium signal transducer 1、 dioxi n - inducible cytochrome P450 (CYP1B1)、 interleukin 1 receptor, type II、 platelet/endothelial cell adhes ion molecule (CD31antigen)、 GRB2~associa ted binding protein 2、 mitogen inducible 2、 transgeliriヽ deleted m live r cancer 1、 8-oxoguanine DNA glycosylase enolase 2， (gamma, neuronal) pinin， desmosome associated protein^ KIAA0367 gene、 KIAA0280 gene、 KIM 1053 protein, KIAA0729 protein、 KIAA1467 protein、 KIAA0716 protein, hyp othetical gene CG018、 hypothetical protein FLJ13612, FLJ90798、 DKFZp586 11823、 および DKFZp5640222 M protein ^ LIM domain binding 2 / CLIM1, myosin right chain kinase (MLC K), myosin, light polypeptide 9, regulatory ^ tropomyosin 1 (alpna cys teine-rich protein 1 (intestinal), reversion-inducing- cysteine-; rich pro tein with kazal motifs, amine oxidase, copper containing 3 (vascular ad hesion protein 1), cytochrome c oxidase subunit Vila polypeptide 1 (muscle), chemokine (C-C motif) ligand 14, ocular development-associated gene, ephrin -B2, Na, K-ATPase subunit alpha 2 (ATP1A2), ATPase, Ca ++ trans porting, ubiquitous ^ aquaporin 9, pleiotrophin N cadherin 19, type 2, WNT inhibitory factor 1, WNTl inducible signaling pathway protein 2, 11—b eta-hydroxys tero id dehydrogenase (HSD11), myelin basic protein (MBP) ゝ pro-galanin, dihydropyrimidinase-like 3, glypican-4 (GPC4), acetylseroto nin 0 ™ methyltransferase ~ like synuclein, gawake a, connective tissue growt factor ^ breast cancer anti-estrogen resistance 3, heat shock 70k Daprotein 2, ets variant gene 1, cAMP-dependent protein kinase subunit RII-beta, microtubule-associated protein, RP / EB family, member 2, ATP-bindin cassette, sub-family C (CFTR / MRP) , member 3, transmembrane 4 superfa mily member 2, AXL receptor tyrosine kinase ^ phospholatnban ゝ re fragment of IgG binding protein ^ microsomal glutathione S-transferase 3, DEPP (decidual protein induced by progesterone), Arg / Ab 1-interacting protein ArgBP2a (ArgBP2a), H0X2H mRNA from the Hox2 locus,; frizzled-related pr otein, G protein-coupled receptor, family C, group 5, member B, GABA-A receptor pi subimit, mesenchyme homeo box 2 (growth arrest-specinc horn eo box) ヽ keratin 7, tumor-- associated calcium signal transducer 1, dioxi n-inducible cytochrome P450 (CYP1B1), interleukin 1 receptor, type II, platelet / endothelial cell adhes ion molecule (CD31antigen), GRB2 ~ associa ted binding protein 2, mitogen inducible 2, transge liri ヽ deleted m live r cancer 1, 8-oxoguanine DNA glycosylase enolase 2, (gamma, neuronal) pinin, desmosome associated protein ^ KIAA0367 gene, KIAA0280 gene, KIM 1053 protein, KIAA0729 protein, KIAA1467 protein, KIAA0716 protein, hypothetical gene CG018, hypothetical protein FLJ13612 , FLJ90798, DKFZp586 11823, and DKFZp5640222
iii)群の遺伝子として好ましい遺伝子： platelet factor 4 (PF4)、 actin, gam ma 2, smooth muscle, entericv interferon (alpha, beta and omega) recept or 2、 DNA topoisomerase I、 CYP3A4、 cycl in-dependent kinase 2、 vascular endothelial growth factor- D、 ABL1N adducin 1 (alpha) isoform G、 KLRC3、 RAB2、 l-acylglycerol-3-phosp ate 0-acyl transferase 2、 tryptase, a丄 pha、 homolog of Yeast RRP4、 MCM3、 hemoglobin, delta、 KIAA1089、 zinc finger p rotein 44 (KOX 7)、 arylacetamide deacetylase (esterase)、 synuc丄 ein， gam ma、 elastase 2, neutrophil^ CYP3A5、 FCGR3A (CD16)、 likely ortholog of m ouse neural in 1、 pyruvate carboxylase^ 2' , 5J -oligoadenylate synthetase 1、 muscle RAS oncogene homology butyrophilin, subfamily 3， member A2、 c onnective tissue activation peptide III、 Ar g/ A 1-inter acting protein Ar gBP2、 FLJ33034 calpain 3 bleomycin hydrolase, desmuslin. TAF6L ESTs (Accession No. AW043812) N FLJ22269、 keratin 7、 scaffold attachment fact or B、 KIAA0346、 interferon, alpha- inducible protein 27、 bridging integr ator 1、 および smooth muscle myosin heavy chain iii) Genes preferred as group genes: platelet factor 4 (PF4), actin, gamma 2, smooth muscle, enteric v interferon (alpha, beta and omega) recept or 2, DNA topoisomerase I, CYP3A4, cycl in-dependent kinase 2, vascular endothelial growth factor- D, ABL1 N adducin 1 (alpha) isoform G, KLRC3, RAB2, l-acylglycerol-3-phospate 0-acyl transferase 2, tryptase, a 丄 pha, homolog of Yeast RRP4, MCM3, hemoglobin, delta, KIAA1089, zinc finger protein 44 (KOX 7), arylacetamide deacetylase (esterase), synuc synein, gam ma, elastase 2, neutrophil ^ CYP3A5, FCGR3A (CD16), likely ortholog of mouse neural in 1, pyruvate carboxylase ^ 2 ', 5 J- oligoadenylate synthetase 1, muscle RAS oncogene homology butyrophilin, subfamily 3, member A2, connective tissue activation peptide III, Ar g / A 1-inter acting protein Ar gBP2, FLJ33034 calpain 3 bleomycin hydrolase, desmuslin.TAF6L ESTs (Accession No.AW043812) N FLJ22269, keratin 7, sc affold attachment fact or B, KIAA0346, interferon, alpha-inducible protein 27, bridging integer 1, and smooth muscle myosin heavy chain
iv)群の遺伝子として好ましい遺伝子： H2B histone family, member G、 cholin ergic receptor, nicotinic, beta polypeptide 4、 related to the N terminu s of tre、 laminin, gamma 2 isoform b、 interleukin 8、 Kruppel -丄 ike facto r 4 (gut) N Al strom syndrome 1、 およぴ occ丄 udin iv) Preferred genes as group genes: H2B histone family, member G, cholin ergic receptor, nicotinic, beta polypeptide 4, related to the N terminus of tre, laminin, gamma 2 isoform b, interleukin 8, Kruppel-丄 ike facto r 4 (gut) N Al strom syndrome 1, and occ 丄 udin
これらの遺伝子はいずれも、 アトピー性皮膚炎患者では発現レベルの変化が 見られなかった遺伝子である。 つまり乾癬患者において特異的に発現レベルが 変化していた遺伝子と言うことができる。 これらの乾癬指標遺伝子の利用によ つて、 乾癬の症状に特異的な治療効果を評価することができる。 All of these genes did not show any change in expression levels in patients with atopic dermatitis. In other words, the expression level specifically in psoriasis patients You can say that the gene has changed. By using these psoriasis indicator genes, therapeutic effects specific to psoriasis symptoms can be evaluated.
本発明において遺伝子の発現レベルを上昇させる化合物とは、 遺伝子の転写、 翻訳、 およおぴ蛋白質の活性発現のいずれかのステップに対して促進的に作用 する作用を持つ化合物である。 また本発明において遺伝子の発現レベルを低下 させる化合物とは、 これらのステップのいずれかに対して阻害的に作用する作 用を持つ化合物である。  In the present invention, a compound that increases the expression level of a gene is a compound that has an action that promotes any of the steps of gene transcription, translation, and protein expression. Further, in the present invention, a compound that reduces the expression level of a gene is a compound that has an effect of inhibiting any of these steps.
本発明のアレルギー性疾患 （または乾癬） 治療候補化合物のスクリーニング 方法は、 in vivoで行うことも in vitroで行うこともできる。 このスクリ一二 ングは、 例えば以下のような工程にしたがって実施することができる。  The method for screening a candidate compound for treating an allergic disease (or psoriasis) of the present invention can be performed in vivo or in vitro. This screening can be performed, for example, according to the following steps.
( 1 ) 被験動物に、 候補化合物を投与する工程、  (1) administering a candidate compound to a test animal,
( 2 ) 前記被検動物の生体試料における指標遺伝子の発現強度を測定する工程、 (2) measuring the expression intensity of the indicator gene in the biological sample of the test animal,
( 3 ) 候補ィヒ合物を接触させない対照と比較して、 a)群、 c)群、 および ）群の いずれか （乾癬の場合は i)群または ii i)群） の指標遺伝子については前記 遺伝子の発現レベルを低下させる化合物を、 また b)群、 d)群、 および d' )群 のいずれか （乾癬の場合は ii)群または iv)群） の指標遺伝子については前 記遺伝子の発現レベルを上昇させる化合物を選択する工程 (3) Compared to the control not contacted with the candidate Eich compound, the indicator gene in any of the groups a), c), and) (for psoriasis, group i) or ii i)) A compound that reduces the expression level of the gene is used as an indicator gene in any one of the groups b), d) and d ') (for psoriasis, the group ii) or iv). Step of selecting a compound that increases the expression level
本発明のスクリーユング方法において、 指標遺伝子としては、 上記 a)〜 、 並びに c，）および d' )のいずれか （乾癬については i) - iv)のいずれか） に記載の 群から選択されたいずれかの遺伝子と機能的に同等な遺伝子を利用することが できる。 本発明において機能的に同等な遺伝子とは、 指標遺伝子によってコー ドされる蛋白質において明らかにされている活性と同様の活性を備えた蛋白質 をコードする遺伝子である。 機能的に同等な遺伝子の代表的なものとしては、 被験動物が本来備えている、 その動物種における指標遺伝子のカウンターパ一 トを挙げることができる。  In the screening method of the present invention, the indicator gene is selected from the group described in any one of the above a) to c) and any one of c,) and d ′) (for psoriasis, any one of i) to iv) Genes functionally equivalent to any of the genes can be used. In the present invention, a functionally equivalent gene is a gene that encodes a protein having an activity similar to the activity clarified in the protein encoded by the indicator gene. A representative example of a functionally equivalent gene is a counterpart of the indicator gene in the animal species that the test animal originally has.
本発明のスクリーニング方法における被験動物としては、 例えばアトピー性 皮膚炎モデル動物を利用することができる。 アトピー性皮膚炎モデル動物は公 知である。 たとえば人間のアトピー性皮膚炎に近いモデルとして、 NC/Ngaマウ スを用いた皮膚炎自然努症モデルが報告されている。 このマウスの耳介にダニ 抗原 （5 i g/耳） を 2-3 日間隔で計 8回投与すると、 2週間以降にはヒ トのァ トピー性皮膚炎に酷似した症状を誘発することができる。 この系に候補化合物 を投与し、 本発明の指標遺伝子の発現レベルの変化を追跡することによって本 発明によるスクリーニングを実施することができる。 As the test animal in the screening method of the present invention, for example, atopic Dermatitis model animals can be used. Atopic dermatitis model animals are known. For example, as a model similar to human atopic dermatitis, a natural dermatitis effort model using NC / Nga mouse has been reported. A total of 8 doses of mite antigen (5 ig / ear) administered to the pinna of this mouse at 2-3 day intervals can induce symptoms very similar to human atopic dermatitis after 2 weeks. . The screening according to the present invention can be performed by administering a candidate compound to this system and tracking the change in the expression level of the indicator gene of the present invention.
このようにして被験動物に薬剤候補化合物を接触させ、 被験動物由来の生体 試料における指標遺伝子の発現に対する化合物の作用をモニターすることによ り、 指標遺伝子の発現レベルに与える薬剤候補化合物の影響を評価することが できる。 被験動物の由来の生体試料における指標遺伝子の発現レベルの変動は、 前記本発明の検査方法と同様の手法によってモニターすることができる。 更に この評価の結果に基づいて、 指標遺伝子が a)群、 c)群、 および c' )群のいずれ 力 (乾癬の場合は i)群または iii)群） に記載の遺伝子である場合には発現レべ ルを低下させる薬剤侯補化合物を、 指標遺伝子が b)群、 d)群、 および d' )群の いずれか （乾癬の場合は ii)群または iv)群） に記載の遺伝子である場合には発 現レベルを上昇させる薬剤候補化合物を選択すれば、 薬剤候補化合物をスクリ 一二ングすることができる。  In this way, by contacting the test animal with the drug candidate compound and monitoring the effect of the compound on the expression of the indicator gene in a biological sample derived from the test animal, the effect of the drug candidate compound on the expression level of the indicator gene is monitored. Can be evaluated. Fluctuations in the expression level of the indicator gene in the biological sample derived from the test animal can be monitored by the same method as the above-described test method of the present invention. Furthermore, based on the results of this evaluation, if the indicator gene is a gene described in any of the groups a), c), and c ') (for psoriasis, the gene is group i) or iii)) Drug candidate compounds that reduce the expression level are identified by the genes listed in b), d) and d ') (for psoriasis, ii) or iv). In some cases, drug candidate compounds can be screened by selecting a drug candidate compound that increases the expression level.
より具体的には、 被験動物から、 皮膚組織試料を採取し、 指標遺伝子の発現 レベルを候補化合物を接触きせない対照と比較することにより、 本発明による スクリーニングを実施することができる。 皮膚組織試料の採取方法、 および調 製方法は公知である。  More specifically, the screening according to the present invention can be performed by collecting a skin tissue sample from a test animal and comparing the expression level of the indicator gene with a control to which a candidate compound cannot be brought into contact. Methods for collecting and preparing skin tissue samples are known.
このようなスクリ一ユングにより、 指標遺伝子の発現に様々な形で関与する 薬剤を選択することができる。 具体的には、 たとえば次のような作用を持つ薬 剤候補化合物を見出すことができる。  Such a screen allows selection of drugs that are involved in various ways in the expression of the indicator gene. Specifically, for example, drug candidate compounds having the following actions can be found.
指標遺伝子が a)群、 c)群、 および c' )群のいずれか （乾癬の場合は i)群または iii)群） に記載の遺伝子である場合： If the indicator gene is one of the groups a), c) and c ') (for psoriasis, iii) When the gene is described in group:
•指標遺伝子の発現をもたらすシグナル伝達経路の抑制  • Suppression of signaling pathways that lead to expression of indicator genes
•指標遺伝子の転写活性の抑制  • Repression of transcriptional activity of indicator gene
•指標遺伝子の転写産物の安定化阻害もしくは分解の促進等  • Inhibition of stabilization or degradation of indicator gene transcripts
指標遺伝芋が b)群、 d)群、 および d' )群のいずれか （乾癬の場合は ii)群または iv)群） に記載の遺伝子である場合： When the indicator genetic potato is a gene described in any of the groups b), d) and d ') (for psoriasis, the group ii) or iv):
•指標遺伝子の発現をもたらすシグナル伝達経路の活性化、  Activation of signaling pathways that lead to the expression of indicator genes,
•指標遺伝子の転写活性の促進、  • promotion of transcriptional activity of indicator genes,
•指標遺伝子の転写産物の安定化や分解の阻害等  • Stabilization and degradation of indicator gene transcripts
また、 in vitroでのスクリーニングにおいては、 例えば、 指標遺伝子を発現 する細胞に候補化合物を接触させ、 指標遺伝子が a)群、 c)群、 および c' )群の いずれか （乾癬の場合は i)群または iii)群） に記載の遺伝子である場合には発 現レベルを低下させる化合物を、 指標遺伝子が b)群、 d)群、 および d' )群のい ずれか （乾癬の場合は ii)群または iv)群） に記載の遺伝子である場合には発現 レベルを上昇させる化合物を選択する方法が挙げられる。 このスクリーニング は、 例えば以下のような工程に従って実施することができる。  In in vitro screening, for example, a candidate compound is brought into contact with cells expressing the indicator gene, and the indicator gene is selected from the group consisting of group a), group c), and group c ') (i. ) Or iii)), a compound that reduces the expression level should be expressed in any of the b), d) and d ') groups (in the case of psoriasis, In the case of the gene described in group ii) or iv), a method for selecting a compound that increases the expression level can be mentioned. This screening can be performed, for example, according to the following steps.
( 1 ) 指標遺伝子を発現する細胞に候補化合物を接触させる工程  (1) a step of bringing a candidate compound into contact with cells expressing the indicator gene
( 2 ) 前記指標遺伝子の発現レベルを測定する工程、  (2) measuring the expression level of the indicator gene,
( 3 ) 侯補ィ匕合物を接触させない対照と比較して、 a)群、 c)群、 および c' )群の いずれか （乾癬の場合は— i)群または iii)群） に記載の指標遺伝子について は前記遺伝子の発現レベルを低下させる化合物を、 また b)群、 d)群、 および d' )群のいずれか （乾癬の場合は i i)群または iv)群） に記載の指標遺伝子に ついては前記遺伝子の発現レベルを上昇させる化合物を選択する工程 本発明において、 指標遺伝子を発現する細胞は、 指標遺伝子を適当な発現べ クターに挿入し、 該ベクターを適当な宿主細胞に導入することにより得ること ができる。 利用できるベクター、 および宿主細胞は、 本発明の指標遺伝子を発 現し得るものであればよい。 宿主一ベクター系における宿主細胞としては、 大 腸菌、 酵母、 昆虫細胞、 動物細胞等が例示でき、 それぞれ利用できるベクター を適宜選択することができる。 (3) As described in any of a) group, c) group, and c ') group (for psoriasis, -i) group or iii) group, as compared to the control not contacted with the Hou-Dani ligated product For the indicator gene of (1), a compound that reduces the expression level of the gene is used, and the indicator described in any one of groups b), d) and d ') (for psoriasis, group ii) or iv) For the gene, a step of selecting a compound that increases the expression level of the gene In the present invention, the cell that expresses the indicator gene inserts the indicator gene into an appropriate expression vector, and introduces the vector into an appropriate host cell Can be obtained by doing so. Available vectors and host cells will produce the indicator gene of the present invention. Anything that can be expressed may be used. Examples of host cells in the host-vector system include Escherichia coli, yeast, insect cells, animal cells, and the like, and available vectors can be appropriately selected.
ベクターの宿主への導入方法としては、 生物学的方法、 物理的方法、 化学的 方法などを示すことができる。 生物学的方法としては、 例えば、 ウィルスべク ターを使用する方法、 特異的受容体を利用する方法、 細胞融合法 (HVJ (センダ ィウィルス）、 ポリエチレングリコール （PEG)、 電気的細胞融合法、 微小核融合 法 （染色体移入)） が挙げられる。 また、 物理的方法としては、 マイクロインジ ェクシヨン法、 エレクト口ポレーシヨン法、 ジーンパーテイク/レガン （gene gu n) を用いる方法が挙げられる。 化学的方法としては、 リン酸カルシウム沈殿法、 リボソーム法、 DEAEデキストラン法、 プロトプラスト法、 赤血球ゴースト法、 赤血球膜ゴースト法、 マイクロカプセル法が挙げられる。  Examples of a method for introducing a vector into a host include a biological method, a physical method, and a chemical method. Biological methods include, for example, a method using a virus vector, a method using a specific receptor, a cell fusion method (HVJ (sendivirus), polyethylene glycol (PEG), an electric cell fusion method, Nuclear fusion method (chromosome transfer)). Examples of the physical method include a microinjection method, an electoral opening method, and a method using a gene part take / regane (gene gun). Chemical methods include calcium phosphate precipitation, ribosome method, DEAE dextran method, protoplast method, erythrocyte ghost method, erythrocyte membrane ghost method, and microcapsule method.
本発明のスクリーエング方法においては、 指標遺伝子を発現する細胞として、 皮膚細胞に加えて、 ランゲルハンス細胞、 マスト細胞、 T細胞、 好酸球、 B細胞、 好中球、 あるいは好塩基球等の皮膚組織に見出される細胞を用いることができ る。  In the screening method of the present invention, in addition to skin cells, skin cells such as Langerhans cells, mast cells, T cells, eosinophils, B cells, neutrophils, or basophils can be used as cells expressing the indicator gene. Cells found in tissues can be used.
ヒト表皮角化細胞 （ケラチノサイト） の初代培養細胞 NHEK (Normal Human Epi dermal Keratinocyte)に対して TGF- j3あるいは sodium butyrate により刺激を 加えることにより分化を誘導することができるという報告がある （例えば Geng Wang ら、 EXPERIMENTAL CELL RESEARCH 198， 27 - 30 (1992))。 分ィヒに伴い corn ied envelope (CE)という細胞内構造物が形成される。 CEの形成あるいは CE構成 分子 (involucrin, loricrinなど）の遺伝子発現を指標として分ィ匕を確認するこ とができる。 こうして分化した細胞は、 本発明におけるスクリーニングに有用 である。  There is a report that differentiation can be induced by stimulating human primary epidermal keratinocytes (keratinocytes), NHEK (Normal Human Epidermal Keratinocyte) with TGF-j3 or sodium butyrate (eg, Geng Wang EXPERIMENTAL CELL RESEARCH 198, 27-30 (1992)). An intracellular structure called corn ied envelope (CE) is formed along with the fraction. The formation of CE or the gene expression of CE constituent molecules (involucrin, loricrin, etc.) can be used as an index to confirm the separation. The cells thus differentiated are useful for screening in the present invention.
皮膚組織に見出される細胞として、 皮膚細胞、 T細胞、 好酸球、 マスト細胞、 好塩基球、 B細胞、 ランゲルハンス細胞、 好中球を利用することもできる。 株化 皮膚細胞は、 均質な細胞を大量に入手できること、 培養が容易なことなどの点 で、 本発明のスクリーニング方法に好適である。 以下に本発明に利用できる皮 膚細胞株の例を示す。 Skin cells, T cells, eosinophils, mast cells, basophils, B cells, Langerhans cells, and neutrophils can also be used as cells found in skin tissue. Stock Skin cells are suitable for the screening method of the present invention in that a large amount of homogeneous cells can be obtained and that culturing is easy. The following are examples of skin cell lines that can be used in the present invention.
一株化皮膚細胞： HaCaT, A431 (ATCC CRL-1555) One cell line: HaCaT, A431 (ATCC CRL-1555)
—株化 T細胞： Jurkat (ATCC TIB- 152) , Molt- 4 (ATCC CRL- 1582) , H9 (ATCC HTB- 176)  —Established T cells: Jurkat (ATCC TIB-152), Molt-4 (ATCC CRL-1582), H9 (ATCC HTB-176)
—株化好酸球： AML14. 3D10  —Eosinophils: AML14. 3D10
一株化マスト細胞： HMC-1 Single cell mast cell: HMC-1
—株化好塩基球： KU-812  —Basic basophils: KU-812
一株化 B細胞： DND39， Raji (ATCC CCL- 86) One cell line B cell: DND39, Raji (ATCC CCL-86)
- (株化） ランゲルハンス細胞： MUTZ - 3  -(Established) Langerhans cells: MUTZ-3
― (株化） 好中球： HL- 60(ATCC CCL- 240)  -Neutrophil: HL-60 (ATCC CCL-240)
株化にカツコをつけたものは、 使用に先だって上記株化細胞から分化させる。 ランゲルハンス細胞（Allan J. Mastersonら Blood 2002 Jul 15 ; 100 (2) : 701-3)、 あるいは好中球（Santos- Beneit AM ら J Leukoc Biol 2000 May ;67 (5) : 712— 24) の分化は公知である。  Those with a click on the cell line are differentiated from the above cell line prior to use. Differentiation of Langerhans cells (Allan J. Masterson et al. Blood 2002 Jul 15; 100 (2): 701-3) or neutrophils (Santos-Beneit AM et al. J Leukoc Biol 2000 May; 67 (5): 712-24) Is known.
スクリーニングの方法は、 まず前記株化皮膚細胞に侯補化合物を接触させる。 その後、 該株化皮膚細胞における指標遺伝子の発現レベルを測定し、 候補化合 物を接触させない対照と比較して、 a)群、 c)群、 および c' )群のいずれか （乾癬 の場合は i)群または iii) ） に記載の指標遺伝子については前記遺伝子の発現 レベルを低下させる化合物を、 また b)群、 d)群、 および d' )群のいずれか （乾 癬の場合は ii)群または iv)群） に記載の指標遺伝子については前記遺伝子の発 現レベルを上昇させる化合物を選択する。  In the screening method, first, a candidate compound is brought into contact with the established skin cells. Thereafter, the expression level of the indicator gene in the established skin cells is measured, and compared with a control not contacted with the candidate compound, any one of the groups a), c), and c ′) (for psoriasis, For the indicator gene described in group i) or iii)), a compound that decreases the expression level of the gene, and any of group b), d) and d ') (ii) for psoriasis) For the indicator gene described in the group or iv), a compound that increases the expression level of the gene is selected.
なお本発明のスクリーニング方法において、 指標遺伝子の発現レベルは、 該 遺伝子がコードする蛋白質の発現レベルのみならず、 対応する mRNAを検出する ことにより比較することもできる。 mRNA によって発現レベルを比較するために は、 蛋白質試料の調製工程に代えて、 先に述べたような mRNA試料の調製工程を 実施する。 mRNAや蛋白質の検出は、 先に述べたような公知の方法によって実施 することができる。 In the screening method of the present invention, the expression level of the indicator gene can be compared not only by the expression level of the protein encoded by the gene, but also by detecting the corresponding mRNA. To compare expression levels by mRNA Performs the mRNA sample preparation step as described above instead of the protein sample preparation step. Detection of mRNA and protein can be carried out by a known method as described above.
さらに本努明の開示に基づいて本発明の指標遺伝子の転写調節領域を取得し、 レポーターァッセィ系を構築することができる。 レポーターアツセィ系とは、 転写調節領域の下流に配置したレポーター遺伝子の発現量を指標として、 該転 写調節領域に作用する転写調節因子をスクリーニングするアツセィ系をいう。 すなわち本発明は、 次の工程を含む、 アトピー性皮膚炎または乾癬の治療薬 のスクリーニング方法であって、 指標遺伝子が、 a)〜 、 並びに c' )および d' ) のいずれか （乾癬の場合は i) - iv)のいずれか） に記載の群から選択されたいず れかの遺伝子、 または指標遺伝子と機能的に同等な遺伝子である方法に関する。  Furthermore, based on the disclosure of this effort, a transcription regulatory region of the indicator gene of the present invention can be obtained, and a reporter assay system can be constructed. The reporter-assay system refers to an atsey system that screens for a transcriptional regulator that acts on the transcriptional regulatory region, using the expression level of a reporter gene located downstream of the transcriptional regulatory region as an index. That is, the present invention provides a method for screening a therapeutic agent for atopic dermatitis or psoriasis, comprising the following steps, wherein the indicator gene is any one of a) to, and c ′) and d ′) (for psoriasis) Relates to a method which is any gene selected from the group described in any of i) to iv) or a gene functionally equivalent to the indicator gene.
( 1 ) 指標遺伝子の転写調節領域と、 この転写調節領域の制御下に発現するレ ポータ一遺伝子を含むベクタ一を導入した細胞と候補化合物を接触させるェ 程、  (1) contacting a candidate compound with a cell into which a vector containing a reporter gene expressed under the control of the transcription regulatory region of the indicator gene and a reporter gene expressed under the control of the transcription regulatory region is introduced;
( 2 ) 前記レポーター遺伝子の活性を測定する工程、 および  (2) measuring the activity of the reporter gene, and
( 3 ) 候補化合物を接触させない対照と比較して、 a)群、 c)群、 および c' )群の いずれか （乾癬の場合は i)群または iii)群） に記載の指標遺伝子について は前記レポーター遺伝子の発現レベルを低下させる化合物を、 また b)群、 d) 群、 および d' )群のいずれか （乾癬の場合は ii)群または iv)群） に記載の指 標遺伝子については前記 ポーター遺伝子の発現レベルを上昇させる化合物 を選択する工程  (3) Compared with the control without contact with the candidate compound, the indicator gene described in any of the groups a), c) and c ') (for psoriasis, the group i) or iii)) A compound that reduces the expression level of the reporter gene, and an indicator gene described in any one of the groups b), d) and d ') (for psoriasis, the group ii) or iv) Selecting the compound that increases the expression level of the porter gene
転写調節領域としては、 プロモーター、 ェンハンサー、 さらには、 通常プロ モーター領域に見られる CMTボックス、 TATAボックス等を例示することができ る。  Examples of the transcription control region include a promoter, an enhancer, and a CMT box, a TATA box, and the like which are usually found in a promoter region.
またレポーター遺伝子としては、 CAT (chloramphenicol acetyl transferase) 遺伝子、 ルシフェラーゼ（lucif erase)遺伝子、 成長ホルモン遺伝子等を利用す ることができる。 As reporter genes, CAT (chloramphenicol acetyl transferase) gene, luciferase (lucif erase) gene, growth hormone gene, etc. are used. Can be
あるいは本 明における各指標遺伝子の転写調節領域を、 次のようにして取 得することもできる。 すなわち、 まず本発明で開示した cDNAの塩基配列に基づ いて、 BACライプラリー、 YACライブラリ一等のヒトゲノム DNAライブラリーか ら、 PCRまたはハイプリダイゼーシヨンを用いる方法によりスクリーニングを行 い、 該 cDNAの配列を含むゲノム DNAクローンを得る。 得られたゲノム DNAの配 列を基に、 本発明で開示した cDMの転写調節領域を推定し、 該転写調節領域を 取得する。 得られた転写調節領域を、 レポーター遺伝子の上流に位置するよう にクローニングしてレポーターコンストラタトを構築する。 得られたレポータ 一コンストラクトを培養細胞株に導入してスクリーニング用の形質転換体とす る。 この形質転換体に候補化合物を接触させ、 候補化合物を接触させない対照 と比較して、 a)群、 c)群、 および c' )群のいずれか （乾癬の場合は i)群または i ii)群） に記載の指標遺伝子については前記レポーター遺伝子の発現レベルを低 下させる化合物を、.また b)群、 d)群、 および d' )群のいずれか （乾癬の場合は i i)群または iv)群） に記載の指標遺伝子については前記レポ一ター遺伝子の発現 レベルを上昇させる化合物を選択することにより本発明のスクリーニングを行 うことができる。  Alternatively, the transcription regulatory region of each indicator gene in the present invention can be obtained as follows. That is, first, based on the nucleotide sequence of the cDNA disclosed in the present invention, screening is performed from a human genomic DNA library such as a BAC library or YAC library by PCR or a method using hybridization, and the cDNA is screened. Obtain a genomic DNA clone containing the sequence. Based on the obtained genomic DNA sequence, the transcription control region of the cDM disclosed in the present invention is estimated, and the transcription control region is obtained. The obtained transcription regulatory region is cloned so as to be located upstream of the reporter gene to construct a reporter construct. The resulting reporter construct is introduced into a cultured cell line to obtain a transformant for screening. One of the groups a), c), and c ') (for psoriasis, group i) or i ii) is compared with a control in which the transformant is contacted with the candidate compound and not contacted with the candidate compound. For the indicator gene described in (2), a compound that reduces the expression level of the reporter gene is used, and any one of the groups b), d) and d ') (for psoriasis, the group ii) or iv With respect to the indicator gene described in (2), the screening of the present invention can be performed by selecting a compound that increases the expression level of the reporter gene.
in vitro での本発明によるスクリーニング方法として、 指標蛋白質の活性に 基づくスクリーニング方法を利用することもできる。 すなわち本発明は、 次の 工程を含む、 ァトピー性皮膚炎の治療薬のスクリ一ユング方法であって、 指標 遺伝子が a)〜 、 並びに c' )および d' )のいずれか （乾癬の場合は i)群 - iv) 群） に記載の群から選択されたいずれかの遺伝子、 または指標遺伝子と機能的 に同等な遺伝子である方法に関する。  As an in vitro screening method according to the present invention, a screening method based on the activity of an indicator protein can also be used. That is, the present invention provides a method for screening a therapeutic agent for atopic dermatitis, which comprises the following steps, wherein the indicator gene is any one of a) to c) and any one of c ′) and d ′) (for psoriasis, i) group-iv) a method which is any gene selected from the group described in group) or a gene functionally equivalent to the indicator gene.
( 1 ) 指標遺伝子によってコードされる蛋白質と候補化合物を接触させる工程、 (1) contacting a protein encoded by the indicator gene with a candidate compound,
( 2 ) 前記蛋白質の活性を測定する工程、 および (2) measuring the activity of the protein, and
( 3 ) 侯補化合物を接触させない対照と比較して、 a)群、 c)群、 および c )群 のいずれか （乾癬の場合は i)群または iii)群） に記載の指標遺伝子につい ては前記活性を低下させる化合物を、 また b)群、 d)群、 および d' )群のい ずれか （乾癬の場合は ii)群または iv)群） に記載の指標遺伝子については, 前記活性を上昇させる化合物を選択する工程 (3) Groups a), c) and c) compared to control without contact with candidate compound (For psoriasis, group i) or group iii)), a compound that decreases the activity, and any one of group b), group d) and group d ') (In the case of psoriasis, group ii) or iv), a step of selecting a compound that increases the activity
本発明における指標蛋白質が有する活性を指標として、 a)群、 c)群、 および c ' )群のいずれか （乾癬の場合は i)群または iii)群） に記載の指標遺伝子につい ては、 その活性を阻害する活性を有する化合物をスクリ一ユングすることがで きる。 このようにして得ることができる化合物は、 a)群、 c)群、 および c' )群の いずれか （乾癬の場合は i)群または iii)群） に記載の各指標遺伝子の働きを抑 制する。 その結果、 皮膚において発現が誘導された指標蛋白質の阻害を通じて、 アトピー性皮膚炎 （または乾癬） を制御することができる。  Using the activity of the indicator protein of the present invention as an indicator, for the indicator gene described in any of the groups a), c) and c ′) (for psoriasis, the group i) or iii)), A compound having an activity of inhibiting the activity can be screened. Compounds obtained in this manner suppress the action of each of the indicator genes described in any of the groups a), c) and c ') (for psoriasis, the groups i) and iii). Control. As a result, atopic dermatitis (or psoriasis) can be controlled through inhibition of an indicator protein whose expression is induced in the skin.
また b)群、 d)群、 および d' )群のいずれか （乾癬の場合は ii)群または iv) 群） に記載の指標遺伝子については、 その活性を促進する活性を有する化合物 をスクリーユングすることができる。 このようにして得ることができる化合物 は、 b)群、 d)群、 および d' )群のいずれか （乾癬の場合は ii)群または iv)群） に記載の指標遺伝子の働きを促進する。 その結果、 皮膚において発現が阻害さ れた指標蛋白質の促進を通じて、 アトピー性皮膚炎 （または乾癬） を制御する ことができる。  For the indicator gene described in any of groups b), d) and d ') (for psoriasis, group ii) or iv), a compound having an activity to promote its activity is screened. can do. The compound thus obtained promotes the function of the indicator gene described in any of the groups b), d) and d ') (for psoriasis, the group ii) or iv) . As a result, atopic dermatitis (or psoriasis) can be controlled through promotion of the indicator protein whose expression is inhibited in the skin.
これらスクリーニングに用いる被験候補物質としては、 ステロイド誘導体等 既存の化学的方法により合成された化合物標品、 コンビナトリァルケミストリ 一により合成された化合物標品のほか、 動 ·植物組織の抽出物もしくは微生物 培養物等の複数の化合物を含む混合物、 またそれらから精製された標品などが 挙げられる。  Test candidate substances used in these screenings include steroid derivatives and other compound specimens synthesized by existing chemical methods, compound specimens synthesized by combinatorial chemistry, extracts of animal and plant tissues, and microorganisms. Examples include a mixture containing a plurality of compounds such as a culture, and a sample purified from the mixture.
本発明による各種のスクリーニング方法に必要な、 ポリヌクレオチド、 抗体、 細胞株、 あるいはモデル動物は、 予め組み合わせてキットとすることができる。 これらのキットには、 標識の検出に用いられる基質化合物、 細胞の培養のため の培地や容器、 陽性や陰性の標準試料、 更にはキットの使用方法を記載した指 示書等をパッケージしておくこともできる。 Polynucleotides, antibodies, cell lines, or model animals required for various screening methods according to the present invention can be combined in advance to form a kit. These kits include substrate compounds used to detect the label, It is also possible to package the culture media and containers, positive and negative standard samples, and instructions and the like describing the use of the kit.
本発明のスクリーニング方法によって選択される化合物は、 アトピー性皮膚 炎の治療薬として有用である。 あるいは、 a)、 c)、 および c，）のいずれかに記載 のいずれかの AD指標遺伝子の発現を抑制することができるアンチセンス DNAも、 ァトピー性皮膚炎の治療薬として有用である。  The compound selected by the screening method of the present invention is useful as a therapeutic agent for atopic dermatitis. Alternatively, antisense DNA that can suppress the expression of any of the AD indicator genes according to any of a), c), and c,) is also useful as a therapeutic agent for atopic dermatitis.
さらに、 a：)、 、 および ）のいずれかに記載されたいずれかの AD指標遺伝 子によってコードされる蛋白質を認識する抗体も、 アトピー性皮膚炎の治療薬 として有用である。 a)、 c)、 および c' )のいずれかに記載された AD指標遺伝子 は、 アトピー性皮膚炎患者の皮疹部において発現が上昇する遺伝子である。 し たがってこれらの遺伝子の発現、 あるいはこれら遺伝子によってコードされる 蛋白質の機能を抑制することによって、 アトピー性皮膚炎の治療効果を期待す ることができる。  Further, an antibody that recognizes a protein encoded by any of the AD indicator genes described in any of a :),, and) is also useful as a therapeutic agent for atopic dermatitis. The AD indicator gene described in any of a), c), and c ′) is a gene whose expression is increased in the rash area of atopic dermatitis patients. Therefore, a therapeutic effect on atopic dermatitis can be expected by suppressing the expression of these genes or the functions of the proteins encoded by these genes.
加えて b)、 d)、 および d' )のいずれかに記載されたいずれかの AD指標遺伝子、 並ぴに該遺伝子によってコードされる蛋白質そのものも、 アトピー性皮膚炎の 治療薬として有用である。  In addition, any of the AD indicator genes described in any of b), d) and d '), and the protein itself encoded by the gene are also useful as a therapeutic agent for atopic dermatitis .
また本発明のスクリーニング方法によって選択される化合物は、 乾癬の治療 薬として有用である。 あるいは、 i)および iii)に記載のいずれかの乾癬指標遺 伝子の発現を抑制することができるアンチセンス DNA も、 乾癬の治療薬として 有用である。 ― '  Further, the compound selected by the screening method of the present invention is useful as a therapeutic agent for psoriasis. Alternatively, an antisense DNA that can suppress the expression of any of the psoriasis indicator genes described in i) and iii) is also useful as a therapeutic agent for psoriasis. ― '
さらに、 i)または iii)に記載されたいずれかの乾癬指標遺伝子によってコー ドされる蛋白質を認識する抗体も、 乾癬の治療薬として有用である。 i)または i ii)に記載された指標遺伝子は、 乾癬患者の皮疹部において発現が上昇する遺伝 子である。 したがってこれらの遺伝子の発現、 あるいはこれら遺伝子によって コードされる蛋白質の機能を抑制することによって、 乾癬の治療効果を期待す ることができる。 加えて ii)または iv)に記載されたいずれかの乾癬指標遺伝子、 並びに該遺伝 子によってコードされる蛋白質そのものも、 乾癬の治療薬として有用である。 本発明のアレルギー性疾患または乾癬の治療薬は、 スクリーニング方法によ つて選択された化合物を有効成分として含み、 生理学的に許容される担体、 賦 形剤、 あるいは希釈剤等と混合することによって製造することができる。 本発 明のアレルギー性疾患または乾癬の治療剤は、 アレルギー症状または乾癬の改 善を目的として、 経口、 あるいは非経口的に投与することができる。 Furthermore, an antibody that recognizes a protein encoded by any of the psoriasis indicator genes described in i) or iii) is also useful as a therapeutic agent for psoriasis. The indicator gene described in i) or i ii) is a gene whose expression is increased in the rash of psoriasis patients. Therefore, a therapeutic effect on psoriasis can be expected by suppressing the expression of these genes or the functions of the proteins encoded by these genes. In addition, any of the psoriasis indicator genes described in ii) or iv) and the proteins themselves encoded by the genes are also useful as therapeutic agents for psoriasis. The therapeutic agent for allergic disease or psoriasis of the present invention contains a compound selected by the screening method as an active ingredient, and is produced by mixing with a physiologically acceptable carrier, excipient, diluent, or the like. can do. The therapeutic agent for allergic disease or psoriasis of the present invention can be administered orally or parenterally for the purpose of ameliorating allergic symptoms or psoriasis.
経口剤としては、 顆粒剤、 散剤、 錠剤、 カプセル剤、 溶剤、 乳剤、 あるいは 懸濁剤等の剤型を選択することができる。 注射剤には、 皮下注射剤、 筋肉注射 剤、 あるいは 0β内 ί¾ 剤等を示すことができる。  As oral preparations, dosage forms such as granules, powders, tablets, capsules, solvents, emulsions, and suspensions can be selected. Examples of the injection include subcutaneous injection, intramuscular injection, and 0β internal preparation.
また、 投与すべき化合物がタンパク質からなる場合には、 それをコードする 遺伝子を遺伝子治療の手法を用いて生体に導入することにより、 治療効果を達 成することができる。 治療効果をもたらすタンパク質をコードする遺伝子を生 体に導入し、 発現させることによって、 疾患を治療する手法は公知である。  When the compound to be administered consists of a protein, a therapeutic effect can be achieved by introducing a gene encoding the protein into a living body using a gene therapy technique. Techniques for treating a disease by introducing a gene encoding a protein that produces a therapeutic effect into an organism and expressing the gene are known.
あるいはアンチセンス DNA は、 適当なプロモーター配列の下流に組み込み、 アンチセンス RNA発現ベクターとして投与することができる。 この発現べクタ 一をアレルギー疾患患者の単核球細胞へ導入すれば、 これらの遺伝子のアンチ センスを発現し、 当該遺伝子の発現レベルの低下によってァレルギ一の治療効 果を達成することができる。 単核球細胞への発現ベクターの導入としては、 in vivo^ あるいは vivoで行う方法が公知である。  Alternatively, antisense DNA can be incorporated downstream of an appropriate promoter sequence and administered as an antisense RNA expression vector. When this expression vector is introduced into mononuclear cells of an allergic disease patient, the antisense of these genes is expressed, and the therapeutic effect of allergy can be achieved by reducing the expression level of the genes. Methods for introducing an expression vector into mononuclear cells are known in vivo and in vivo.
投与量は、 患者の年齢、 性別、 体重および症状、 治療効果、 投与方法、 処理 時間、 あるいは該医薬組成物に含有される活性成分の種類などにより異なるが、 通常成人一人あたり、 一回につき 0, 1 mgから 500 mgの範囲で、 好ましくは 0. 5 mgから 20 mgの範囲で投与することができる。 しかし、 投与量は種々の条件に より変動するため、 上記投与量よりも少ない量で充分な場合もあり、 また上記 の範囲を超える投与量が必要な場合もある。 また本発明は、 a)群〜 d)群、 並びに ）群および d' )群のいずれかから選択さ れた少なくとも 1種類の AD指標遺伝子を測定するためのプローブを固定したァ トビー性皮膚炎の診断用 DNAチップを提供する。 あるいは本発明は、 i)群〜 iv) 群のいずれかから選択された少なくとも 1種類の乾癬指標遺伝子を測定するた めのプローブを固定した乾癬の診断用 DNAチップを提供する。 The dose varies depending on the age, sex, weight and condition of the patient, therapeutic effect, administration method, treatment time, or the type of active ingredient contained in the pharmaceutical composition. It can be administered in the range of 1 mg to 500 mg, preferably in the range of 0.5 mg to 20 mg. However, since the dosage varies depending on various conditions, a dosage lower than the above-mentioned dosage may be sufficient, and a dosage exceeding the above-mentioned range may be required in some cases. Further, the present invention provides artby's dermatitis immobilized with a probe for measuring at least one AD indicator gene selected from the groups a) to d), and any of the groups) and d '). A DNA chip for diagnosis. Alternatively, the present invention provides a DNA chip for diagnosing psoriasis, on which a probe for measuring at least one type of psoriasis indicator gene selected from any of groups i) to iv) is immobilized.
測定すべき指標遺伝子の種類は任意である。 指標遺伝子の数が多いほど、 多 くの指標に基づく判断が可能となる。 一般に、 より多くの指標を測定する方が、 診断の確度は高まる。 また、 複数の指標遺伝子を測定する場合には、 性質の異 なった遺伝子を選択するのが有利である。 発現レベルの変動のメカニズム、 あ るいは遺伝子によってコードされる蛋白質の機能などが異なると考えられる遺 伝子は、 相互に性質の異なる遺伝子と言うことができる。 更に、 a) -d)並びに c ' )および d' )に記載された AD指標遺伝子と i) -iv)に記載された乾癬指標遺伝子 とを測定対象とすることによって、 アトピー性皮膚炎と乾癬の両方を同一の DNA チップによつて検查することもできる。  The type of indicator gene to be measured is arbitrary. The greater the number of indicator genes, the more judgments can be made based on more indicators. In general, measuring more indicators increases the accuracy of the diagnosis. When measuring a plurality of indicator genes, it is advantageous to select genes having different properties. Genes that are considered to have different expression level mechanisms or different functions of the proteins encoded by the genes can be referred to as genes having mutually different properties. Furthermore, atopic dermatitis and psoriasis can be measured by targeting the AD indicator gene described in a) -d) and c ') and d') and the psoriasis indicator gene described in i) -iv). Both can be detected by the same DNA chip.
指標遺伝子の み合せの例として、 次のような例を示すことができる。 次に 示すような指標遺伝子の組み合せは、 ァレルギ一の検査の精度の向上に貢献す る。  The following example can be shown as an example of combining indicator genes. The following combinations of indicator genes contribute to the improvement of the accuracy of allergic tests.
[プロテアーゼとプロテアーゼインヒビターで構成される群に含まれる指標遺 伝子から選択された 2以上の遺伝子]  [Two or more genes selected from indicator genes included in the group consisting of proteases and protease inhibitors]
プロテアーゼとプロテアーゼインヒビターとは、 組織の崩壊と構築のパラン スの指標となる。 すなわち、 本発明における指標遺伝子のうち、 プロテアーゼ 群に含まれる遺伝子と、 プロテアーゼインヒビターに含まれる遺伝子から選択 された遺伝子について、 その遺伝子検出用のプローブを集積して、 アトピー性 皮膚炎検查用チップとすることができる。 各群に含まれる指標遺伝子は、 明細 書の最後に示した指標遺伝子のリストから見出すことができる。 例えば、 匪 P - 3 (Matrix Metalloproteinase-3)と TIMP- 1 (Tissue Inhibitor of MMP- 1)の不均衡 により皮疹が慢性化するような報告もあることから、 プロテアーゼとプロテア ーゼィンヒビターの組み合せはァレルギ一性疾患の指標遺伝子の組み合せとし て意義がある。 Proteases and protease inhibitors are indicators of a balance between tissue disruption and architecture. That is, among the indicator genes of the present invention, for a gene selected from the genes included in the protease group and the gene included in the protease inhibitor, a probe for detecting the gene is integrated, and a chip for detecting atopic dermatitis is obtained. It can be. The indicator genes included in each group can be found from the list of indicator genes shown at the end of the description. For example, the imbalance between marauder P-3 (Matrix Metalloproteinase-3) and TIMP-1 (Tissue Inhibitor of MMP-1) It has been reported that the eruption may cause chronic rash. Therefore, the combination of protease and protease inhibitor is significant as a combination of indicator genes for allergic monogenic disease.
[サイト力イン、 サイ ト力インレセプター、 ケモカイン、 ケモカインレセプ ター、 CD抗原、 抗体、 および抗体レセプターで構成される群に含まれる指標遺 伝子から選択された 2以上の遺伝子]  [Two or more genes selected from the indicator genes included in the group consisting of cytoforce, site force receptors, chemokines, chemokine receptors, CD antigens, antibodies, and antibody receptors]
これらの組み合せは、 いずれも相互にリガンドとレセプターの関係にある物 質の組み合せである。 免疫応答は、 これらの物質間の相互作用の結果と見るこ ともできる。 したがって、 これらの指標遺伝子を組み合せることによって、 皮 膚組織が免疫学的にどのような状態にあるかを判断できる可能性がある。 指標 遺伝子としては、 リガンドとレセプターの関係にある分子の両方を選択しても 良いし、 本発明における指標遺伝子としていずれか一方しか示されていない場 合には、 いずれか一方のみを指標遺伝子として選択することもできる。  Each of these combinations is a combination of substances that are in a mutual relationship between a ligand and a receptor. The immune response can also be viewed as the result of an interaction between these substances. Therefore, by combining these indicator genes, it may be possible to determine the state of skin tissue immunologically. As the indicator gene, both a ligand and a receptor-related molecule may be selected, or when only one of them is indicated as the indicator gene in the present invention, only one of them is used as the indicator gene. You can also choose.
[サイト力イン、 細胞外マトリックス蛋白質、 細胞骨格系の蛋白、 細胞間接 着分子、 および転写因子で構成される群に含まれる指標遺伝子から選択された 2以上の遺伝子]  [Two or more genes selected from indicator genes included in the group consisting of cytokinin, extracellular matrix proteins, cytoskeletal proteins, cell indirect adhesion molecules, and transcription factors]
細胞外マトリックス蛋白質としてはコラーゲンなどを示すことができる。 細 胞骨格系の蛋白は、 ケラチン、 small prolin rich protein, involucrinなどを 含む。 また、 細胞間接着分子には、 カドヘリン、 デスモコリンなどが含まれる。 そして、 転写因子としては、 jun、 fos、 あるいは myc を示すことができる。 こ れらの指標遺伝子の発現レベルを観察することによって、 皮膚組織の分化、 炎 症部位の再構築 （修復） の度合を評価できる可能性がある。  Examples of extracellular matrix proteins include collagen and the like. Cytoskeletal proteins include keratin, small prolin rich protein, involucrin, and others. In addition, intercellular adhesion molecules include cadherin, desmocholine and the like. The transcription factor can be jun, fos, or myc. By observing the expression levels of these indicator genes, it may be possible to evaluate the degree of skin tissue differentiation and the remodeling (repair) of the inflammatory site.
[酵素に含まれる指標遺伝子から選択された 2以上の遺伝子]  [Two or more genes selected from the indicator genes contained in the enzyme]
酵素に含まれる指標遺伝子を選択することによって、 皮膚細胞 （epidermal k eratinocyteや dermal fibroblast)でどのような代謝が行われているかを知る ことができる。 例えば、 脂質メディエーターやパリア機能を支える脂質分子の 代謝については脂質代謝酵素の発現レベルから判断することができる。 脂質代 儲ォ酵 には、 たと；^は pnospholipase A2、 cyclooxygenase— 2、 prostaglandin D 2 synthase, あるいは Fatty acid desaturase 1， 2などが含まれる。 By selecting the indicator gene contained in the enzyme, it is possible to know what kind of metabolism is performed in skin cells (epidermal keratinocyte and dermal fibroblast). For example, lipid mediators and lipid molecules that support Paria function Metabolism can be determined from the expression level of lipid metabolizing enzymes. In the case of lipid fermentation fermentation, ^ includes pnospholipase A2, cyclooxygenase-2, prostaglandin D 2 synthase, or Fatty acid desaturase 1,2.
あるいは、 より精度の高い検査を実現するために、 a)群および b)群を構成す る遺伝子から選択された任意の複数の遺伝子の組み合せについて、 選択された 遺伝子を検出することができるプローブを集積したァトピー性皮膚炎検査用チ ップは有効である。 具体的には、 a)群から通常 1 0以上、 たとえば 3 0以上、 好ましくは 5 0以上、 より好ましくは 6 0以上、 更に好ましくは 8 0以上、 あ るいは 1 0 0以上の遺伝子を選択することができる。 一方 b)群からは、 通常 1 0以上、 たとえば 3 0以上、 好ましくは 5 0以上、 より好ましくは 6 0以上、 更に好ましくは 8 0以上の遺伝子を選択することができる。  Alternatively, in order to realize a more accurate test, a probe capable of detecting the selected gene is selected for any combination of a plurality of genes selected from the genes constituting the groups a) and b). The accumulated tips for atopic dermatitis testing are effective. Specifically, a gene of at least 10 or more, for example, 30 or more, preferably 50 or more, more preferably 60 or more, further preferably 80 or more, or 100 or more is selected from the group a). can do. On the other hand, from group b), usually 10 or more, for example, 30 or more, preferably 50 or more, more preferably 60 or more, and still more preferably 80 or more genes can be selected.
同様に、 より精度の高い検査を実現するために、 c)群、 d)群、 c' )群、 および d' )群を構成する遺伝子から選択された任意の複数の遺伝子の組み合せについて、 選択された遺伝子を検出することができるプローブを集積したアトピー性皮膚 炎検査用チップは有効である。 具体的には、 c)群および Zまたは c' )群から通常 1 0以上、 たとえば 3 0以上、 好ましくは 5 0以上、 より好ましくは 6 0以上、 更に好ましくは 8 0以上の遺伝子を選択することができる。 一方 d)群および/" または d' )群からは、 通常 1 0以上、 たとえば 3 0以上、 好ましくは 5 0以上、 より好ましくは 6 0以上、 更に好ましくは 7 0以上の遺伝子を選択することが できる。 ― '  Similarly, in order to achieve a more accurate test, select any combination of multiple genes selected from the genes constituting the c) group, the d) group, the c ′) group, and the d ′) group. A chip for atopic dermatitis testing that integrates probes capable of detecting the detected gene is effective. Specifically, genes of usually 10 or more, for example, 30 or more, preferably 50 or more, more preferably 60 or more, more preferably 80 or more are selected from the group c) and the group Z or c ′). be able to. On the other hand, from the d) group and / or or d ') group, a gene of usually 10 or more, for example, 30 or more, preferably 50 or more, more preferably 60 or more, and still more preferably 70 or more should be selected. -'
また、 a)群から選択された遺伝子と c)群および/または c' )群から選択され た遺伝子の組み合せからなるァトピー性皮膚炎検査用チップも、 検査精度を高 めるために有効である。 同様に、 b)群から選択された遺伝子と d)群および/ま たは d'；)群から選択された遺伝子の組み合せからなるァトピー性皮膚炎検査用チ ップも、 検査精度を高めるために有効である。  Atopic dermatitis testing chips comprising a combination of a gene selected from group a) and a gene selected from group c) and / or c ') are also effective for increasing the test accuracy. . Similarly, a tip for atopic dermatitis testing consisting of a combination of a gene selected from group b) and a gene selected from group d) and / or d ';) may be used to increase the testing accuracy. It is effective for
更に前記 i)〜iv)に記載された乾癬指標遺伝子を組み合わせることによって、 本発明による乾癬検査用チップを得ることができる。 乾癬指標遺伝子は、 前記 のアトピ一性皮膚炎検査用チップと同様にして組み合わせることができる。 なお本明細書において引用された全ての先行技術文献は、 参照として本明細書 に組み入れられる。 図面の簡単な説明 Further, by combining the psoriasis indicator genes described in the above i) to iv), A psoriasis test chip according to the present invention can be obtained. The psoriasis indicator gene can be combined in the same manner as in the atopic dermatitis test chip described above. All prior art documents cited in the present specification are incorporated herein by reference. BRIEF DESCRIPTION OF THE FIGURES
図 1は、 アトピー性皮膚炎患者および健常人皮膚組織における IL- 4遺伝子の 発現量を示すグラフである。 図中、 縦軸は IL - 4遺伝子のコピー数、 横軸は解析 に用いた皮膚組織の症例を示す。  FIG. 1 is a graph showing the expression level of the IL-4 gene in skin tissues of patients with atopic dermatitis and healthy subjects. In the figure, the vertical axis shows the copy number of the IL-4 gene, and the horizontal axis shows the skin tissue cases used in the analysis.
図 2は、 アトピー性皮膚炎患者および健常人皮膚組織における IL- 13遺伝子 の発現量を示すグラフである。 図中、 縦軸は IL-13遺伝子のコピー数、 横軸は 解析に用いた皮膚組織の症例を示す。  FIG. 2 is a graph showing the expression level of the IL-13 gene in skin tissues of patients with atopic dermatitis and healthy subjects. In the figure, the vertical axis shows the copy number of the IL-13 gene, and the horizontal axis shows the skin tissue cases used for the analysis.
図 3は、 アトピー性皮膚炎患者おょぴ健常人皮膚組織における IL- γ遺伝子の 発現量を示すグラフである。 図中、 縦軸は IL - γ遺伝子のコピー数、 横軸は解析 に用レ、た皮膚組織の症例を示す。 発明を実施するための最良の形態  FIG. 3 is a graph showing the expression level of the IL-γ gene in the skin tissue of a healthy patient with atopic dermatitis. In the figure, the vertical axis shows the copy number of the IL-γ gene, and the horizontal axis shows the skin tissue cases used for analysis. BEST MODE FOR CARRYING OUT THE INVENTION
以下、 本発明を実施例に基づいてより具体的に説明する。  Hereinafter, the present invention will be described more specifically based on examples.
〔実施例 1〕 アトピー性皮膚炎患者皮膚組織における、 ァフィメトリックス 社ジ一ンチップによるディラアレンシャル発現解析  [Example 1] Analysis of the expression of Dila arenal in skin tissue of patients with atopic dermatitis using Affimetrics Genchip
ァトピー性皮膚炎患者の皮膚組織で発現変動している新しい治療標的遺伝子 あるいは診断に有用な遺伝子を見出すことを目的として、 アトピー性皮膚炎患 者の無疹部、 急性病変部と健常人の正常皮膚で発現している遺伝子について、 ジーンチップを用いたディファレンシャルな発現比較解析を行つた。  In order to find new therapeutic target genes whose expression levels fluctuate in the skin tissue of patients with atopic dermatitis or genes useful for diagnosis, the normal and normal areas of atopic dermatitis patients without eruptions and acute lesions For genes expressed in the skin, differential expression analysis using a gene chip was performed.
( 1 ) 皮膚検体の入手  (1) Obtaining skin samples
アトピー性皮膚炎患者 12例、 健常人 4例から同意を得て、 患者からは無疹部 と急性病変部を、 健常人からは正常皮膚を、 各部位からそれぞれ 3個の皮膚検 体 （直径 3腿） を採取した。 急性病変部位は S本皮膚科学会の診断基準 （日本皮 膚科学会誌 104 : 1210 (1994) ) に基づき判定した。 皮膚を採取したアトピー性 皮膚炎患者の臨床情報を表 1に示す。 Consent was obtained from 12 patients with atopic dermatitis and 4 from healthy subjects. And acute lesions, normal skin from healthy subjects, and three skin specimens (three thighs) from each site. The site of the acute lesion was determined based on the diagnostic criteria of the Japanese Society of Dermatology (Journal of the Japanese Dermatological Association 104: 1210 (1994)). Table 1 shows the clinical information of atopic dermatitis patients whose skin was collected.
表 1  table 1
Figure imgf000098_0001
Figure imgf000098_0001
*：特異的 IgEはクラス 1〜 6に分類され、 クラス 3以上が陽性  *: Specific IgE is classified into classes 1 to 6, positive for class 3 or higher
( 2 ) ヒト皮膚からのジーンチップ解析用の匪調製  (2) Preparation of bandits for analysis of gene chips from human skin
採取した 3個の皮膚 biopsy (直径 3mm) を Isogen (日本ジーン；和光純薬） に浸漬し、 ウルトラタックス T8ホモジナイザー （IKA社） を使用してホモジナ ィズした。 ホモジナイズ以降の操作は Isogenのマニュアルに従い、 total RNA を抽出した。 クロ口ホルムを加え、 攪拌遠心して水層を回収した。 次にイソプ ロバノールを加え、 攪拌遠心して沈殿を回収した。 沈殿は 75%エタノールでリ ンス、 遠心を行い、 沈殿を total RNAとして回収した。 回収した total RNAは R Neasy Mini kit (QIAGEN) を用い、 そのマニュアルに従って更に精製した。  The three skin biopsy (3 mm in diameter) collected were immersed in Isogen (Nippon Gene; Wako Pure Chemical Industries) and homogenized using an Ultratax T8 homogenizer (IKA). After homogenization, total RNA was extracted according to the manual of Isogen. A black-mouthed form was added, and the mixture was centrifuged with stirring to collect an aqueous layer. Next, isopropanol was added, and the mixture was centrifuged with stirring to collect the precipitate. The precipitate was rinsed with 75% ethanol and centrifuged, and the precipitate was collected as total RNA. The collected total RNA was further purified using the R Neasy Mini kit (QIAGEN) according to the manual.
( 3 ) ジーンチップ用の cDNA合成 Total RNA 2— 5 g力 ら、 T7— (dT) 24 (Amersham Pharmacia Biotech) をプライ マーとして、 Affymetrix社の Expression Analysis Technical Manualの方法に 従 ヽ、 Superscript II Reverse Transcriptase (Life Technologies社) を用レヽ て逆転写し、 1本鎖 cDNAを作製した。 (3) cDNA synthesis for gene chip From 2-5 g of total RNA, use T7— (dT) 24 (Amersham Pharmacia Biotech) as a primer and use Superscript II Reverse Transcriptase (Life Technologies) according to the method of Affymetrix Expression Analysis Technical Manual. And reverse transcribed to produce single-stranded cDNA.
T7 - (dT)24プライマーは、 以下のように T7プロモーターの塩基配列に（dT) 24を 付加した塩基配列からなる。 The T7-(dT) 24 primer consists of a nucleotide sequence obtained by adding (dT) 24 to the nucleotide sequence of the T7 promoter as follows.
T7-(dT) 24プライマー： 5' -GGCCAGTGAATTGTAATACGACTCACTATAGGGAGGCGG - (dT) 2 4-3' (配列番号： 4 7 ) T7- (dT) 24 primer: 5 '-GGCCAGTGAATTGTAATACGACTCACTATAGGGAGGCGG - (dT) 2 4 -3' ( SEQ ID NO: 4 7)
次こ、 Expression Analysis Technical Manual ίこ従レヽ、 DNA Ligase, DNA pol ymerase Iおよび RNase Hを加え、 2本鎖 cDNAを合成した。 cDNAをフエノー ル.クロ口ホルム抽出後、 Phase Lock Gelsに供し、 エタノール沈殿により精製 した。  Next, Expression Analysis Technical Manual, DNA Ligase, DNA polymerase I and RNase H were added to synthesize double-stranded cDNA. After extracting the cDNA with phenol-chloroform, it was subjected to Phase Lock Gels and purified by ethanol precipitation.
さらに、 BioArray High Yield RNA Transcription Labeling Kit を用い、 ビ ォチンラベルした cRNAを合成した。 RNeasy Spin column (QIAGEN)を用いて cRN Aを精製し、 熱処理により断片化した。  Furthermore, biotin-labeled cRNA was synthesized using the BioArray High Yield RNA Transcription Labeling Kit. CRNA was purified using an RNeasy Spin column (QIAGEN) and fragmented by heat treatment.
そのつち 10 /i gの cRNAを Expression Analysis Technical Manualに従い Hyb ridization Cocktailに加えた。 これを DNAチップに入れ、 45°Cで 16時間ハイ ブリダィゼ一ションした。 DNAチップとしては GeneChip(R) Human Genome U95Av2 (Affymetrix社製） を用いた。 10 / ig of cRNA was added to the hybridization cocktail according to the Expression Analysis Technical Manual. This was placed on a DNA chip and hybridized at 45 ° C for 16 hours. GeneChip (R) Human Genome U95Av2 (Affymetrix) was used as a DNA chip.
DNAチップを洗浄した後、' Streptavidin— Phycoerythrinを加え染色した。 洗 浄後、 normalャギ IgGとピオチン化ャギ抗ストレプトアビジン IgG抗体の混合 液をアレイに加えた。 さらに、 蛍光強度を増強する目的で、 再度 Streptavidin -Phycoerythrinを加え染色した。 洗浄後、 スキャナーにセットし、 DNAチップ 解析ソフトにて解析した。  After washing the DNA chip, 'Streptavidin-Phycoerythrin was added and stained. After washing, a mixture of normal goat IgG and a biotinylated goat anti-streptavidin IgG antibody was added to the array. Furthermore, in order to enhance the fluorescence intensity, Streptavidin-Phycoerythrin was added again for staining. After washing, it was set on a scanner and analyzed with DNA chip analysis software.
( 4 ) 丽チップ解析  (4) Chip analysis
DNAチップ解析ソフトである Suiteを用いて発現蛍光強度を測定し、 データ解 析を行った。 まず全てのチップについて Absolute analysis を行い、 用いたサ ンプル各々の遺伝子発現量を測定した。 Measure the expression fluorescence intensity using Suite, a DNA chip analysis software, and analyze the data. The analysis was performed. First, Absolute analysis was performed for all chips, and the gene expression level of each sample used was measured.
1 transcript に対応するチップデータの解析は、 プローブセクトのパーフエ クトマツチとミスマッチの蛍光強度を比較して、 positiveと negativeを決定し た。 Positive Fraction, Log Avg, Pos/Negの値から判定される Absolute Call である P (present)、 A (absent)、 および M (marginal)の 3 区分の判定を行つ た。 用語定義は以下に示した。  In the analysis of the chip data corresponding to 1 transcript, the positive and negative were determined by comparing the fluorescence intensity of the mismatch between the probe match and the probe match. Three categories of P (present), A (absent), and M (marginal), which are absolute calls determined from the values of Positive Fraction, Log Avg, and Pos / Neg, were performed. Term definitions are shown below.
Positive Fraction; Positiveなペアの割合 Positive Fraction; Positive pair ratio
Log Avg; パーフエクトマツチとミスマッチのプローブセルの蛍光強度比の対数 の平均  Log Avg; Average of logarithm of fluorescence intensity ratio between perfect match and mismatched probe cell
Pos/Neg; Positiveペア数と Negativeペア数の比  Pos / Neg; Ratio of Positive pairs to Negative pairs
また、 パーフエクトマツチとミスマッチのプローブセルの蛍光強度の差の平 均値である Average Difference (Avg Diff)も計算した。  The average difference (Avg Diff), which is the average value of the difference between the fluorescence intensity of the perfect match and that of the mismatched probe cell, was also calculated.
サンプル間の遺伝子発現を比較する場合には、 GeneChip Analysis Suite Use r Guideに従レヽ Comparison analysisを行った。 各チップの全プロープセットの 蛍光強度の平均値が一定になるように蛍光強度を補正した。  When comparing gene expression between samples, a comparative analysis was performed according to the GeneChip Analysis Suite User Guide. The fluorescence intensity was corrected so that the average value of the fluorescence intensity of all probe sets of each chip was constant.
ァトピー性皮膚炎患者の無疹部と急性病変部間で発現変動する遺伝子の解析 Analysis of genes whose expression fluctuates between rash and acute lesions in patients with atopic dermatitis
11 例の各患者の無疹部における遺伝子発現と急性病変部における遺伝子発現 を Comparison analysis によって比較解析し、 急性病変部で無疹部と比べて 2 倍以上発現が増加している遺伝子、 1/2以下に発現が減少している遺伝子を選択 した。 患者ごとに選んできた遺伝子について、 今度は 11例の患者のうち 6例以 上で共通変動している遺伝子を選択した。 選択した遺伝子の遺伝子名と各症例 における発現プロファイルを表 2〜表 9に示した。 複数のァトピー性皮膚炎患 者で共通変動しているこれらの遺伝子はァトピー性皮膚炎の病態形成に重要な 役割を果たしていると考えられ、 診断マーカーや治療のターゲットとしての重 要性が示唆される。 0 0 アトピー性皮膚炎患者の急性病変部と無疹部間の比較で、 急性病変部で発現 が増加していた遺伝子を示した。 表中に記載されている、 † T† ΐは変動が 50 倍以上、 ΐ† ΐは 10〜50倍、 ††は 3〜10倍、 †は 2〜3倍、 一は変動なし、The gene expression in the rash-free area and the gene expression in the acute lesion in each of 11 patients were compared and analyzed by comparison analysis, and the genes whose expression was more than 2-fold higher in the acute lesion than in the rash-free area were compared. Genes whose expression decreased to 2 or less were selected. Of the genes selected for each patient, we now select genes that are commonly fluctuating in more than six of the eleven patients. Tables 2 to 9 show the gene names of the selected genes and the expression profiles in each case. These genes, which are commonly fluctuated in multiple patients with atopic dermatitis, are thought to play an important role in the pathogenesis of atopic dermatitis, suggesting their importance as diagnostic markers and therapeutic targets. You. 0 0 A comparison between acute lesions and non-rashes in patients with atopic dermatitis showed genes whose expression was increased in the acute lesions. In the table, † T † ΐ has a variation of 50 times or more, ΐ † 10 10 to 50 times, †† 3 to 10 times, † 2 to 3 times, one has no change,
I 4 i i « 1/50倍以下、 I 1 I ι/5θ〜ι/ιο倍、 I 1は ι/ιο〜： L/3倍、 Iは ιI 4 i i «1/50 or less, I 1 I ι / 5θ ~ ι / ιο times, I 1 is ι / ιο ~: L / 3 times, I is ι
/3〜1/2倍であることを示す。 / 3 to 1/2 times.
0 表 2— 1
Figure imgf000102_0001
0 Table 2-1
Figure imgf000102_0001
.02ί 表 2— 2
Figure imgf000103_0001
0 3 .02ί Table 2-2
Figure imgf000103_0001
0 3
表 2— 3
Figure imgf000104_0001
表 2— 4 Table 2—3
Figure imgf000104_0001
Table 2—4
Figure imgf000105_0001
• 05 表 3— 2
Figure imgf000106_0001
表 3— 3
Figure imgf000105_0001
• 05 Table 3-2
Figure imgf000106_0001
Table 3—3
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000107_0001
Figure imgf000108_0001
表 4一
Figure imgf000108_0002
. 0 8; 表 4— 2
Figure imgf000109_0001
- 0 9ぐ 表 4— 3
Figure imgf000110_0001
Table 41
Figure imgf000108_0002
. 0 8; Table 4-2
Figure imgf000109_0001
-0 9
Figure imgf000110_0001
表 5— 1 Table 5-1
Figure imgf000111_0001
- 11; 表 5— 2
Figure imgf000112_0001
表 5— 3
Figure imgf000111_0001
-11; Table 5-2
Figure imgf000112_0001
Table 5-3
Figure imgf000113_0001
表 6— 1
Figure imgf000113_0001
Table 6-1
ァトピー性皮膚炎患者の急性病変と無疹部間の比較で、 急性病変部で発現が 減少していた遺伝子を示した。 表中に記載されている、 ††† ΐは変動が 50倍 以上、 † † †は 10〜50倍、 † ΐは 3〜： 10倍、 ΐは 2〜3倍、 一は変動なし、 丄 丄 は 1/50倍以下、 丄 丄 丄は 1/50〜1/10倍、 丄 Iは 1/10〜1/3倍、 は 1/3 〜1/2倍であることを示す。  Comparison between acute lesions and non-rashes in patients with atopic dermatitis showed genes whose expression was decreased in the acute lesions. In the table, 変 動 変 動 indicates that the fluctuation is 50 times or more, † † 10 is 10 to 50 times, † 3 is 3 to 10 times, ΐ is 2-3 times, 一 is no change, 一丄 indicates 1/50 or less, 丄 丄 indicates 1/50 to 1/10, 倍 I indicates 1/10 to 1/3, and indicates 1/3 to 1/2.
Human Human Human Human
Fold Change Fold Change
3正 症 症 症 症 症 症 症 ¾E 症 症  (3) Syndrome Syndrome Syndrome Syndrome
accessi  accessi
例 例 例 例 例 例 例 例 例 例 例 Ρ値 Descriptions 2 on  Example Example Example Example Example Example Example Example Example Example Example Example Ρ Value Descriptions 2 on
3 4 6 9 10 12 13 15 16 17  3 4 6 9 10 12 13 15 16 17
Protease  Protease
M2562  M2562
246一 at U U 1 U U U 0.0033 kallikreinl  246 one at U U 1 U U U 0.0033 kallikreinl
9  9
4071乙 at U U 1 U U U 0.0619 AB0019 cat epsin V  4071 Otsu at U U 1 U U U 0.0619 AB0019 cat epsin V
28 表 6— 2 28 Table 6-2
Figure imgf000114_0001
4： 表 6— 3
Figure imgf000114_0001
4: Table 6—3
Figure imgf000115_0001
一 1
Figure imgf000115_0001
One one
Figure imgf000115_0002
Figure imgf000115_0002
Figure imgf000116_0001
Figure imgf000116_0001
.16: 表 7— 3
Figure imgf000117_0001
.16: Table 7—3
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000118_0001
表 8— 2 Table 8-2
Figure imgf000119_0001
Figure imgf000119_0001
protein protein
Figure imgf000120_0001
Figure imgf000120_0001
. 2 0; . 2 0;
表 9一 2  Table 9-1 2
Figure imgf000121_0001
ァトピー性皮膚炎患者の無疹部と健常人の正常組織間で発現変動する遺伝子の 解析
Figure imgf000121_0001
Analysis of genes whose expression fluctuates between the eruption area of atopic dermatitis patients and normal tissues of healthy persons
12例の各患者の無疹部における遺伝子発現と健常人 1例の正常組織における 遺伝子発現を Comparison analysis によって比較解析し、 患者無疹部で健常皮 膚と比べて 2倍以上努現が増加している遺伝子、 1/2以下に発現が減少している 遺伝子を選択した。 患者ごとに選んできた遺伝子について、 今度は 12例の患者 のうち 7例以上で共通して発現が増加している遺伝子、 12例の患者のうち 8例 以上で共通して発現が減少している遺伝子を選択した。 選択した遺伝子から、 健常人 3例間の比較により健常皮膚において発現が安定しない遺伝子を除いた。 9808 Comparison analysis of gene expression in the eruption area of each of 12 patients and gene expression in the normal tissue of one healthy subject was performed by comparison analysis, and the effort was more than doubled in the eruption area of the patients compared to the healthy skin. Genes whose expression was reduced to 1/2 or less were selected. Regarding the genes selected for each patient, the genes whose expression is commonly increased in 7 or more of 12 patients, and whose expression is decreased in 8 or more of 12 patients Selected genes. From the selected genes, genes whose expression was not stable in healthy skin were excluded by comparison among three healthy subjects. 9808
1 2 1; \ 1 2 1; \
最終的に選択した遺伝子の遺伝子名と各症例における発現プロフアイルを表 1 0〜表 1 2およぴ表 1 3〜表 1 5に示した。 健常人と比べてァトピー性皮膚炎 患者の皮膚で発現が増減している遺伝子はァトピー'性皮膚炎癸症の一因となつ ている可能性があり、 皮疹ができてから治療するのではなく、 皮疹ができる前 に治療するための診断マーカ一や治療のターゲットとして重要であると考えら れる。 The gene names of the finally selected genes and the expression profiles in each case are shown in Tables 10 to 12 and Tables 13 to 15. Genes with increased or decreased expression in atopic dermatitis skin compared to healthy individuals may play a role in atopic dermatitis syringitis, rather than treating after skin eruption However, it is considered to be important as a diagnostic marker for treatment before skin eruption or as a target for treatment.
表 1 0— 1  Table 1 0— 1
アトピー性皮膚炎患者の無疹部と健常人の正常組織間の比較で、 患者の無疹 部で発現が増加していた遺伝子を示した。 表中に記載されている、 † † † †は 変動が 50倍以上、 † † ΐは 10〜50倍、 ΐ †は 3〜： L0倍、 †は 2〜3倍、 —は 変動なし、 丄丄丄丄は 1/50倍以下、 丄丄丄は 1/50〜： L/10倍、 Iは 1/10〜1/3  A comparison between the rash-free area of patients with atopic dermatitis and the normal tissue of healthy subjects showed genes whose expression was increased in the rash-free area of patients.変 動 † † 変 動 、 変 動 50 変 動 50 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 な し 変 動 変 動 3 L な し な し L L L な し L L な し L L丄 丄 丄 is 1/50 or less, 丄 丄 丄 is 1/50 or more: L / 10 times, I is 1/10 to 1/3
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000122_0001
Figure imgf000123_0001
表 10— 2
Figure imgf000123_0002
表 1 0— 3 Table 10-2
Figure imgf000123_0002
Table 10-3
Figure imgf000124_0001
表 1 1— 1
Figure imgf000124_0001
Table 1 1— 1
Gu protein 1 Gu protein 1
DDX21: DEAD/H (Asp-DDX21: DEAD / H (Asp-
40490—at ί ί T ί † ί †T ί ί U41387 40490—at ί ί T ί † ί † T ί ί U41387
Glu-Ala- Asp/His) box polypeptide 21 Glu-Ala- Asp / His) box polypeptide 21
41209一 at † TT † Τί TT lipoprotein ί ί Μ15856 41 209 at † TT † Τί TT lipoprotein ί Μ Μ15856
lipase lipase
41642一 at ίί ί † TT TT † ί Χ75940 SMA5 表 1 1一 2 41642-at ίί ί † TT TT † ί 94075940 SMA5 Table 1 1 1 2
Figure imgf000125_0001
表 1 1一 3
Figure imgf000125_0001
Table 1 1 1 3
Figure imgf000126_0001
表 1 2
Figure imgf000126_0001
Table 1 2
Figure imgf000127_0001
表 1 2— 2
Figure imgf000127_0001
Table 1 2— 2
Figure imgf000128_0001
Figure imgf000128_0001
表 1 3— 1 Table 13-1
ァトピー性皮膚炎患者の無疹部と健常人の正常組織間の比較で、 患者の無疹 部で発現が減少していた遺伝子を示した。 表中に記載されている、 † † † †は 変動が 50倍以上、 † † †は 10〜50倍、 ††は 3〜： L0倍、 ΐは 2〜3倍、 —は 変動なし、 丄丄丄 ·[は 1/50倍以下、 丄 丄は 1/50〜： 1/10倍、 丄 は 1/10〜： 1/3 倍、 丄は 1/3〜： 1/2倍であることを示す。  A comparison between the rash-free area of atopic dermatitis patients and the normal tissue of healthy subjects showed genes whose expression was decreased in the rash-free areas of patients. In the table, 変 動 † † † has a fluctuation of 50 times or more, † † 10 10 to 50 times, †† 3 to: L0 times, ΐ 2 to 3 times, — indicates no change, 丄[· [Is 1/50 or less, 丄 1 is 1/50 ~: 1/10 times, 丄 is 1/10 ~: 1/3 times, 丄 is 1/3 ~: 1/2 times Is shown.
Figure imgf000129_0001
Figure imgf000130_0001
1 3 Oi 表 1 4一
Figure imgf000131_0001
表 1 4一 2
Figure imgf000129_0001
Figure imgf000130_0001
1 3 Oi Table 1 4 1
Figure imgf000131_0001
Table 14 1 2
Figure imgf000132_0001
表 1 5— 2
Figure imgf000132_0001
Table 15-2
Figure imgf000133_0001
5 - 3
Figure imgf000133_0001
5-3
Figure imgf000134_0001
Figure imgf000134_0001
( 5 ) 統計解析  (5) Statistical analysis
アトピー性皮膚炎患者の無疹部と急性病変部の比較解析の場合は、 チップ解 析時の Average Difference値を用い、 ウィルコクソン符号付順位和検定 （Wile oxon signed-ranks test) を行つた。 統計解析により算出された p値は表 2〜 表 9に記載した。  For the comparative analysis of rash-free and acute lesions in patients with atopic dermatitis, a Wilcoxon signed-ranks test was performed using the Average Difference value at the time of chip analysis. The p-values calculated by the statistical analysis are described in Tables 2 to 9.
〔実施例 2〕 ヒトのァトピー性皮膚炎とマウス皮膚炎モデルの比較  [Example 2] Comparison of human atopic dermatitis and mouse dermatitis model
ヒトアトピー性皮膚炎の無疹部と皮疹部間で発現変動している遺伝子とマウ ス皮膚炎モデルの非感作皮膚と感作皮膚間で発現変動している遺伝子を比較解 析した。 两者の間で共通して変動している遺伝子群を選ぶことができれば、 そ の遺伝子についてノックァゥトマウスあるいはトランスジエニックマウスを作 製することにより、 皮膚炎病態におけるその遺伝子の重要性を評価することが できる。  Genes whose expression was fluctuated between the eruption and eruption areas of human atopic dermatitis and genes whose expression was fluctuated between non-sensitized skin and sensitized skin of the mouse dermatitis model were comparatively analyzed. If a gene group that fluctuates in common among individuals can be selected, knockout mice or transgenic mice for that gene will be created to evaluate the importance of that gene in dermatitis pathology can do.
また、 その遺伝子が液性因子あるいは膜蛋白質をコードしている場合には、 中和抗体、 液性因子そのもの、 あるいは可溶性レセプターなどを実験動物に投 与することができる。 その結果、 遺伝子改変マウスを利用した場合に比べて短 期間で、 その遺伝子のヒト皮膚炎病態における重要性を評価できる。 ヒトのァ トビー性皮膚炎の皮膚検体を用いた遺伝子発現解析によって見出された病態関 連遺伝子の重要性を評価する目的で、 マウス皮膚炎モデルの遺伝子プロフアイ ルを解析し、 ヒトのアトピー性皮膚炎と比較した。 When the gene encodes a humoral factor or a membrane protein, a neutralizing antibody, the humoral factor itself, or a soluble receptor can be administered to the experimental animal. As a result, the importance of the gene in human dermatitis pathological conditions can be evaluated in a shorter time than when a genetically modified mouse is used. Pathophysiology found by gene expression analysis using skin specimens of human atby dermatitis To evaluate the importance of the linked genes, we analyzed the gene profile of a mouse dermatitis model and compared it with human atopic dermatitis.
( 1 ) NC/Ngaマウス皮膚炎モデルの作製  (1) Preparation of NC / Nga mouse dermatitis model
SPF NC/Ngaマウス （ · 6週齢） の耳介部と背部皮膚にダニ抗原 （Dermat ophagoides pteronyssinus 5 /z g /部位） を 3 日間隔で計 9回皮内投与した。 耳浮腫の測定と背部皮膚の症状を週 1回の割合で観察した。 血中の total IgE濃 度については、 ダニ抗原投与前、 投与開始 14 日後、 28 日後に採血を行い、 マ ウス IgE測定キット （ャマサ醤油） にて測定した。 コントロールとして非感作 群を取り、 各群 20匹 （10匹：ダニ抗原投与開始 14 日後解剖、 10匹：ダュ抗 原投与開始 28 S後解剖） で試験を行った。  Mite antigen (Dermat ophagoides pteronyssinus 5 / zg / site) was intradermally administered to the auricle and back skin of SPF NC / Nga mice (6 weeks old) 9 times at 3 day intervals in total. Ear edema measurements and back skin symptoms were observed weekly. Blood was collected for total IgE concentration before mite antigen administration, 14 days after administration, and 28 days after administration, and measured with a mouse IgE measurement kit (Yamasa soy sauce). As a control, a non-sensitized group was taken, and the test was carried out using 20 animals (10 animals: dissected 14 days after the start of mite antigen administration, 10 animals: 28 S after the start of Dau antigen administration).
ダニ抗原投与 14 日後解剖および 28 日解剖のいずれの試験においても非感作 群では耳浮腫は認められなかった。 一方、 感作群ではダニ抗原投与 1週間後よ り明らかな耳の肥厚を示し、 2週間後以降高値を維持した （表 1 6 )。 また、 血 中の total IgE濃度は、 感作群においてダニ抗原投与 2週間後より濃度の上昇が 認められた （表 1 7 )。 これらの結果に加え、 病理学的検査の結果、 感作群の耳 介皮膚では、 表皮の肥厚、 真皮と皮下組織には炎症性細胞浸潤 （好中球、 好酸 球ならびにリンパ球)、 浮腫、 結合組織の増生およびマスト細胞の脱顆粒等が軽 度から中等度の変化で観察され、 皮膚炎病態を形成していることが確認できた。 Ear edema was not observed in the non-sensitized group in both the 14-day and 28-day dissection tests of the tick antigen. On the other hand, in the sensitized group, ear thickening became apparent more than one week after the administration of the tick antigen, and the value was kept high after two weeks (Table 16). Further, total I g E concentration in the blood, increasing concentrations than after mite antigen administration 2 weeks in sensitized group was observed (Table 1 7). In addition to these results, pathological examination showed that in the auricle skin of the sensitized group, epidermal thickening, inflammatory cell infiltration into dermis and subcutaneous tissue (neutrophils, eosinophils and lymphocytes), edema However, proliferation of connective tissue, degranulation of mast cells, etc. were observed with slight to moderate changes, confirming that dermatitis was formed.
表 1 6  Table 16
ダニ抗原感作期間中の耳浮腫の変化を示した。 耳浮腫率 (％)  Changes in ear edema during mite antigen sensitization were demonstrated. Ear edema rate (%)
感作期間 (weeks)  Sensitization period (weeks)
1 2 3 4 非感作群 Mean 102 107 106 109  1 2 3 4 Non-sensitized group Mean 102 107 106 109
土 S£. 3 4 3 3 感作群 Mean 189 271 286 278  Sat. S £. 3 4 3 3 Sensitization group Mean 189 271 286 278
土 S.E. 5 6 5 6 耳浮腫率 （％) =感作後の耳の厚さ/感作前の耳の厚さ X 100 表 1 7 Sat SE 5 6 5 6 Ear edema rate (%) = Ear thickness after sensitization / Ear thickness before sensitization X 100 Table 17
ダニ抗原感作期間中の血中 total IgE濃度の推移を示した。  The change of the blood total IgE concentration during the mite antigen sensitization period was shown.
Figure imgf000136_0001
Figure imgf000136_0001
( 2 ) マウス皮膚からめジーンチップ解析用の RNA調製  (2) RNA preparation for gene chip analysis from mouse skin
非感作マウスおよび感作マウス （感作後 14 日と 28 日） より耳介皮膚および 背部皮膚を回収し、 Isogen (日本ジーン；和光純薬） に浸漬し、 ホモジナイザ 一 （NS-310E ; (株） 日音医理科器械製作所)を使用して氷冷下にホモジナイズ した。 ホモジナイズ以降の操作は Isogenのマニュアルに従い、 total RNAを抽 出した。 クロ口ホルムを加え、 攪拌遠心して水層を回収した。 次にイソプロパ ノールを加え、 攪拌遠心して沈殿を回収した。 沈殿は 75%エタノーノレでリンス、 遠心を行い、 沈殿を total RNAとして回収した。 回収した total RNAは RNea sy Mini kit (QIAGEN)を用い、 そのマニュアルに従って更に精製した。  Ear skin and back skin were collected from unsensitized mice and sensitized mice (14 and 28 days after sensitization), immersed in Isogen (Nippon Gene; Wako Pure Chemical Industries), and homogenized with NS-310E; Homogenized under ice-cooling using Nichion Medical Science Instrument Co., Ltd.). After homogenization, total RNA was extracted according to the manual of Isogen. A black-mouthed form was added, and the mixture was centrifuged with stirring to collect an aqueous layer. Next, isopropanol was added, and the mixture was centrifuged with stirring to collect the precipitate. The precipitate was rinsed with 75% ethanol and centrifuged, and the precipitate was collected as total RNA. The collected total RNA was further purified using the RNeasy Mini kit (QIAGEN) according to the manual.
( 3 ) ジーンチップ用の cDNA合成  (3) cDNA synthesis for gene chip
1群 10匹の各個体の耳介から抽出した total RNAをまとめ、 その total RN A 2— 5〃 g力 ら、 T7-(dT)24 Aiiiersham Pharmacia Biotech) をプライマーと して、 Afiymetri 子土の Expression Analysis Technical Manual の方法に従い、 Superscript II Reverse Transcriptase (Life Technologies社) を用いて逆早 ·κ 写し、 1本鎖 cDNAを作製した。  The total RNA extracted from the pinna of each individual of 10 animals per group was collected, and T7- (dT) 24 Aiiiersham Pharmacia Biotech) was used as a primer, and the total RNA extracted from Afiymetri cotyledons was used. According to the method of Expression Analysis Technical Manual, reverse pre-kappa copy was performed using Superscript II Reverse Transcriptase (Life Technologies) to prepare single-stranded cDNA.
T7-(dT)24プライマーは、 以下のように T7 プロモーターの塩基配列に (dT)24 を付加した塩基配列からなる。 The T7- (dT) 24 primer consists of a nucleotide sequence obtained by adding (dT) 24 to the nucleotide sequence of the T7 promoter as follows.
T7-(dT)24プライマー： 5' -GGCCAGTGAATTGTAATACGACTCACTATAGGG AGGCGG - (dT)24-3' (配列番号： 4 7 ) T7- (dT) 24 primer: 5'-GGCCAGTGAATTGTAATACGACTCACTATAGGG AGGCGG-(dT) 2 4-3 '(SEQ ID NO: 47)
次に、 Expression Analysis Technical Manualに従レヽ、 DNA Ligase, DNA polymerase Iおよび RNase Hを加え、 2本鎖 cDNAを合成した。 cDNAを フエノール'クロ口ホルム抽出後、 Phase Lock Gels に供し、 エタノール沈殿 により精製した。  Next, according to Expression Analysis Technical Manual, DNA Ligase, DNA polymerase I and RNase H were added to synthesize a double-stranded cDNA. After extracting the cDNA with phenol-form, it was subjected to Phase Lock Gels and purified by ethanol precipitation.
らに、 BioArray High "iield RNA Transcription Labeling Kit 用い、 ビォチンラベルした cRNA を合成した。 RNeasy Spin colunm(QIAGEN)を用 いて cRNAを精製し、 熱処理により断片化した。  Furthermore, biotin-labeled cRNA was synthesized using the BioArray High “iield RNA Transcription Labeling Kit. The cRNA was purified using RNeasy Spin colunm (QIAGEN) and fragmented by heat treatment.
そのつち lO ti gの cRNAを Expression Analysis Technical Manualに従い Hybridization Cocktailに加えた。 これを DNAチップに入れ、 45°Cで 16時間 ハイプリダイゼーションした。 DNAチップとしては GeneChip(R> Murine Gen ome U74Av2, Bv2, Cv2 (Affymetrix社製） を用いた。 The lOti g cRNA was added to the Hybridization Cocktail according to the Expression Analysis Technical Manual. This was placed in a DNA chip and hybridized at 45 ° C for 16 hours. GeneChip (R > Murine Genome U74Av2, Bv2, Cv2 (Affymetrix)) was used as a DNA chip.
DNAチップを洗浄した後、 Streptavidin— Phycoerythrin を加え染色した。 洗浄後、 normalャギ IgG とビォチン化ャギ抗ストレプトアビジン IgG抗体の 混合液をアレイに加えた。 さらに、 蛍光強度を増強する目的で、 再度 Streptavi din -Phycoerythrin を加え染色した。 洗浄後、 スキャナーにセットし、 DNA チップ解析ソフトにて解析した。  After washing the DNA chip, Streptavidin-Phycoerythrin was added for staining. After washing, a mixture of normal goat IgG and biotinylated goat anti-streptavidin IgG antibody was added to the array. Furthermore, for the purpose of enhancing the fluorescence intensity, Streptavidin-Phycoerythrin was added again for staining. After washing, it was set on a scanner and analyzed with DNA chip analysis software.
( 4 ) DNAチップ解析  (4) DNA chip analysis
DNAチップ解析ソフトである Suiteを用いて発現蛍光強度を測定し、 データ 解析を行った。 まず全てのチップについて GeneChip Analysis Suite User G uide に従い Absolute analysis を行い、 用いたサンプル各々の遺伝子発現量を 測定した。  The expression fluorescence intensity was measured using Suite, a DNA chip analysis software, and the data was analyzed. First, Absolute analysis was performed on all chips according to the GeneChip Analysis Suite User Guide, and the gene expression level of each sample used was measured.
1 transcript に対応するチップデータの解析は、 プローブセットのパーフエ クトマツチとミスマッチの蛍光強度を比較して、 positive と negative を決定し た。 Positive Fraction, Log Avg, Pos/Ne の値から判定される Absolute Call である P (present)、 A (absent) , およぴ M (marginal)の 3 区分の判定を行 つた。 用語定義は以下に示した。 In the analysis of the chip data corresponding to 1 transcript, the positive and negative were determined by comparing the fluorescence intensity of the mismatch and the mismatch of the probe set. Positive Fraction, Log Avg, Pos / Ne are determined from three categories: P (present), A (absent), and M (marginal), which are absolute calls. I got it. Term definitions are shown below.
Positive Fraction; Positiveなペアの割合 Positive Fraction; Positive pair ratio
Log Avg;パ一フエクトマツチとミスマッチのプローブセルの蛍光強度比の対数 の平均  Log Avg; Average of logarithm of ratio of fluorescence intensity between performance match and mismatched probe cell
Pos/Neg; Positiveペア数と Negativeペア数の比  Pos / Neg; Ratio of Positive pairs to Negative pairs
また、 パーフエクトマツチとミスマッチのプローブセルの蛍光強度の差の平 均値である Average DifFerence(Avg Difif)も計算した。  In addition, Average DifFerence (Avg Difif), which is the average value of the difference in fluorescence intensity between the perfect match and the mismatched probe cell, was also calculated.
サンプル間の遺伝子発現を比較する場合には、 GeneChip Analysis Suite Us er Guideに従い Comparison analysisを行った。 チップ間の補正は、 各チップ の全プローブセットの蛍光強度の平均値が一定になるように補正を行った。  When comparing gene expression between samples, Comparison analysis was performed according to the GeneChip Analysis Suite User Guide. The correction between chips was performed so that the average value of the fluorescence intensity of all probe sets of each chip was constant.
ダニ抗原感作皮膚と非感作皮膚間で発現変動する遺伝子 Gene whose expression fluctuates between mite antigen-sensitized skin and non-sensitized skin
感作マウス耳介皮膚における遺伝子発現と非感作マゥス耳介皮膚における遺 伝子発現を Comparison analysisによって比較解析し、 感作 14日後あるいは 2 8日後のマウス耳介皮膚において非感作耳介皮膚と比べて 2倍以上発現が増加し ている遺伝子 （データ 5 ) および 1/2以下に発現が減少している遺伝子 （デー タ 6 ) を選択した。 これら遺伝子群とヒ トのアトピー性皮膚炎の無疹部と急性 病変部間で発現変動した遺伝子群を比較した結果を表 1 8〜表 2 0に示した。 共通変動を示した遺伝子については、 このマウス皮膚炎モデルにおいてノック ァゥトマウスあるいはトランスジエニックマウスを作製することにより、 皮膚 炎病態における重要性を評価することができる。 また、 液性因子や膜蛋白質に ついては皮膚炎モデルマウスに中和抗体を投与、 あるいは液性因子そのものや 可溶性膜蛋白質を投与することにより、 その遺伝子の重要性を評価できる。  Comparative analysis of gene expression in sensitized mouse auricle skin and gene expression in non-sensitized mouse auricle skin was performed by comparison analysis, and non-sensitized auricle skin was detected 14 or 28 days after sensitization. Genes whose expression was increased more than 2-fold (data 5) and genes whose expression was reduced to less than 1/2 (data 6) were selected. Tables 18 to 20 show the results of comparison between these gene groups and the gene groups whose expression was fluctuated between the non-rash area and the acute lesion area of human atopic dermatitis. Genes showing common variation can be evaluated for their significance in dermatitis pathology by producing knockout mice or transgenic mice in this mouse dermatitis model. For humoral factors and membrane proteins, the importance of the genes can be evaluated by administering neutralizing antibodies to dermatitis model mice, or by administering humoral factors themselves or soluble membrane proteins.
表 1 8— 1  Table 18-1
ヒ トのアトピー性皮膚炎 （急性病変部と無疹部） と NC/Nga マウス皮膚炎モ デル （ダニ感作耳介皮膚と非感作耳介皮膚） 間で共通変動 （増加） した遺伝子 を示した。 表中に記載されている、 †† † ΐは変動が 50倍以上、 †† ΐは 10 〜50倍、 卞 卞は3〜10倍、 †は 2〜3倍、 一は変動なし、 丄 丄 丄 丄は 1/50倍以 下、 丄 丄 丄は 1/50〜： 1/10倍、 丄 丄は 1/10〜： 1/3倍、 丄は 1/3〜： 1/2倍であること を示す。 Genes that were commonly altered (increased) between human atopic dermatitis (acute lesions and eruptions) and NC / Nga mouse dermatitis models (mite-sensitized and non-sensitized auricle skin) were identified. Indicated. As shown in the table, 変 動 † 変 動 fluctuates more than 50 times, †† ΐ 10 ~ 50 times, Byeon Byeon is 3 ~ 10 times, 2 is 2-3 times, は is no change, 丄 丄 丄 以 is 1/50 or less, / 丄 丄 is 1/50 ~: 1/10 times,丄 1 indicates 1/10 to: 1/3 times, and 丄 indicates 1/3 to: 1/2 times.
Figure imgf000139_0001
表 1 8— 2
Figure imgf000139_0001
Table 18-2
Figure imgf000140_0001
Figure imgf000141_0001
表 1 9一
Figure imgf000140_0001
Figure imgf000141_0001
Table 19
Immunoglobulin, Immunoglobulin  Immunoglobulin, Immunoglobulin
receptor, and related molecule  receptor, and related molecule
丄 IgG low affinity Fc 丄 IgG low affinity Fc
37688 a ΤΤ 37688 a ΤΤ
ί ί ίί ίί ίί ίί ίί Μ31312 Μ31932 fragment receptor t ί  Μ ί ίί ίί ίί ίί ίί Μ 1231312 Μ31932 fragment receptor t ί
jcRlla)一  jcRlla)
Kinase and Kinase and
_ Phosphatase  _ Phosphatase
hemopoietic cell protein-tyrosine hemopoietic cell protein-tyrosine
2045 s at ■ TT J03023 M16592 2045 s at ■ TT J03023 M16592
kinase (HCK) , clone HK24 HPTP epsilon I mRNA for protein kinase (HCK), clone HK24 HPTP epsilon I mRNA for protein
32916 at T† D83484 X54134 tyrosine phosphatase epsilon ― 1 4 32916 at T † D83484 X54134 tyrosine phosphatase epsilon ― 14
Figure imgf000142_0001
4 2 表 2 0
Figure imgf000142_0001
4 2 Table 2 0
ヒトのアトピー性皮膚炎 （急性病変部と無疹部） と NC/Ngaマウス皮膚炎モデ ル （ダニ感作耳介皮膚と非感作耳介皮膚） 間で共通変動 （減少） した遺伝子を 示した。 表中に記載されている、 † † T †は変動が 50倍以上、 † † †は 10〜50 倍、 ΐ †は 3〜10倍、 ΐは 2〜3倍、 一は変動なし、 丄 丄 丄 丄は 1/50倍以下、 丄 丄 丄は 1/50〜1/10倍、 丄 は 1/10〜： 1/3倍、 丄は 1/3〜1/2倍であることを 示す。 Genes that show a common variation (decrease) between human atopic dermatitis (acute lesions and no eruptions) and NC / Nga mouse dermatitis model (mite-sensitized and non-sensitized auricles) Was. In the table, † 変 動 T † fluctuates 50 times or more, † † 10 10 to 50 times, ΐ 3 3 to 10 times, ΐ 2 to 3 times, one does not change, 、 丄丄 丄 indicates 1/50 or less, 丄 丄 1 indicates 1/50 to 1/10 times, 丄 indicates 1/10 to: 1/3 times, and 丄 indicates 1/3 to 1/2 times.
Human Human Mouse H umanHuman Human Mouse Human
Fold Change Fold Change Fold Change Fold Change
Probe No.症例 2 症例 4症例 6症例 9症例 10症例 12症例 13症例 15症例 16症例 17 14曰目 28曰目 accession accession Descriptions Probe No. case 2 case 4 case 6 case 9 case 10 case 12 case 13 case 15 case 16 case 17 14 statement 28 statement accession accession Descriptions
Cytoske eta I structural protein, cytoskeleton associated protein Cytoske eta I structural protein, cytoskeleton associated protein
sciellin  sciellin
35105一 at i 11 Π I I 11 Π i u I AA727482 AF045941 (SCEL)  35 105 i at i 11 Π I I 11 Π i u I AA727482 AF045941 (SCEL)
Transcription factor and related molecule (Transcriptional regulator protein ) Transcription factor and related molecule (Transcriptional regulator protein)
Inhibitor of DNA binding 4 Inhibitor of DNA binding 4
41536 at U Π 11 a I a u I AJ001972 AL022726 ( ID4 ) 41536 at U Π 11 a I a u I AJ001972 AL022726 (ID4)
Others Others
39930一 at U I u u ill Ui 1 I L77867 D83492 EphB6  39930 one at U I u u ill Ui 1 I L77867 D83492 EphB6
retinol binding retinol binding
32552— at 1 u u u i u u II U63146 X00129 protein 4 32552—at 1 u u u i u u II U63146 X00129 protein 4
metallothionei metallothionei
521— at Π U u I u u u u I U07808 U0丽 n lV (MTIV) 521—at Π U u I u u u u I U07808 U0 丽 n lV (MTIV)
DKFZp564D20 DKFZp564D20
39577— at I i I I I u 1 AI841913 AL050024 6 39577—at I i I I I u 1 AI841913 AL050024 6
3 1：
Figure imgf000145_0001
3 1:
Figure imgf000145_0001
以上の解析の結果に基づいて、 ァトピー性皮膚炎の指標とすることができる 遺伝子として次に示す遺伝子を同定した。 これらの遺伝子は、 いずれも本発明 における指標遺伝子として用いることができる。 以下に示す各遺伝子のデータ は、 いずれも、 左から順に次の情報を記載している。 各情報はスラッシュ （/) で区切って示している。 また指標遺伝子は、 各遺伝子の機能にしたがって、 分 類した。 分類された機能を=で示した。  Based on the results of the above analysis, the following genes were identified as genes that can be used as indicators of atopic dermatitis. Any of these genes can be used as an indicator gene in the present invention. Each of the data for each gene shown below lists the following information in order from the left. Each piece of information is separated by a slash (/). The indicator genes were classified according to the function of each gene. Classified functions are indicated by =.
「遺伝子名およぴシンボル」  "Gene name and symbol"
「プローブ」 （GeneChipにおけるプローブ ID)  "Probe" (Probe ID in GeneChip)
「プロ一プの塩基配列のデザィンのために用いられた塩基配列のデータベース (GenBank)ァクセッションナンパー」  "Database of base sequence used for designing base sequence of the program (GenBank) accession number"
「各指標遺伝子の塩基配列のデータベース（GenBank)ァクセッションナンパ一」 「各指標遺伝子によってコードされるアミノ酸配列のデータベース（GenBank)ァ クセッションナンパー」  "Database (GenBank) accession number database for each index gene" "Database (GenBank) accession number database for amino acid sequences encoded by each index gene"
["Referencej (当該遺伝子を報告した論文、 および塩基配列を配列表に記載し たものについてはその配列番号）  ["Referencej (for the paper reporting the gene, and for the nucleotide sequence listed in the sequence listing, its SEQ ID number)"
一データ 1 One data 1
(アトピー性皮膚炎患者の皮疹部における発現レベルが、 同一の患者の無疹部 に比べて高い指標遺伝子群）  (Indicator genes whose expression level in the rash area of patients with atopic dermatitis is higher than that in the rash area of the same patient)
==Protease and associated molecule= == Protease and associated molecule =
cathepsin C/133_at/X87212/ M_001814/NP_001805/FEBS Lett. 369 (2-3)， 326 - 3 30 (1995) cathepsin C / 133_at / X87212 / M_001814 / NP_001805 / FEBS Lett. 369 (2-3), 326-30 (1995)
metalloproteinase (HME) /1481_at/L23808/NM_002426/NP_002417 /J. Biol. Chem.metalloproteinase (HME) / 1481_at / L23808 / NM_002426 / NP_002417 / J. Biol. Chem.
268 (32) , 23824-23829 (1993) 268 (32), 23824-23829 (1993)
airway trypsin— like protease /31345_at/AB002134/N _004262/NP_004253/J. Bi ol, Chem. 273 (19) , 11895—11901 (1998) airway trypsin— like protease / 31345_at / AB002134 / N _004262 / NP_004253 / J. Biol, Chem. 273 (19), 11895—11901 (1998)
type IV collagenase /31859_at/J05070/NM_004994/NP_004985/J. Biol. Chem. I type IV collagenase / 31859_at / J05070 / NM_004994 / NP_004985 / J. Biol. Chem. I
264 (29) , 17213-17221 (1989)  264 (29), 17213-17221 (1989)
cathepsin Z precursor (CTSZ) /32514_s_at/AF032906/NM_001336/NP_001327/J. Biol. Chem. 273 (27)， 16816-16823 (1998) cathepsin Z precursor (CTSZ) / 32514_s_at / AF032906 / NM_001336 / NP_001327 / J. Biol. Chem. 273 (27), 16816-16823 (1998)
disintegrin- protease /34974_at/Y13323/ M_014479/NP_055294 /J. Exp. Med. 1 86 (5) , 655-663 (1997) disintegrin-protease / 34974_at / Y13323 / M_014479 / NP_055294 / J. Exp.Med. 186 (5), 655-663 (1997)
serine protease-like protein /37137_at/M17016/NM_004131/NP_004122 /J. I腿 unol. 139 (1) , 250-256 (1987) serine protease-like protein / 37137_at / M17016 / NM_004131 / NP_004122 /J.I thigh unol. 139 (1), 250-256 (1987)
pro-cathepsin L (major excreted protein MEP) /37391— at/ X12451/ML001912 /NP— 001903/J. Clin. Invest. 81 (5) , 1621 - 1629 (1988) pro-cathepsin L (major excreted protein MEP) / 37391— at / X12451 / ML001912 / NP— 001903 / J. Clin. Invest. 81 (5), 1621-1629 (1988)
protease M /37554_at/U62801/NM_002774/NP_002765/Biochim. Biophys. Acta 1 350 (1) , 11-14 (1997) protease M / 37554_at / U62801 / NM_002774 / NP_002765 / Biochim. Biophys. Acta 1 350 (1), 11-14 (1997)
skin collagenase /38428_at/M13509/NM_002421/NP_002412 /J. Biol. Chem. 261skin collagenase / 38428_at / M13509 / NM_002421 / NP_002412 / J. Biol. Chem. 261
(14) , 6600-6605 (1986) (14), 6600-6605 (1986)
trypsinogen IV b-form /40043_at/X71345/NM_007343/NP_031369 /Gene 136 (1 - 2) , 167—175 (1993) trypsinogen IV b-form / 40043_at / X71345 / NM_007343 / NP_031369 / Gene 136 (1-2), 167-175 (1993)
SPUVE (protease, serine, 23) /40078—at/AF015287/ M— 007173/NP— 009104/配列番 号： 1 (塩基配列） 配列番号： 2 (アミノ酸配列）  SPUVE (protease, serine, 23) / 40078—at / AF015287 / M—007173 / NP— 009104 / SEQ ID NO: 1 (base sequence) SEQ ID NO: 2 (amino acid sequence)
Proprotein convertase subtilisin/kexin type 1/40649— at/X64810/NM—000439/NP —000430 /FEBS Lett. 300 (1)， 82-88 (1992)  Proprotein convertase subtilisin / kexin type 1 / 40649—at / X64810 / NM—000439 / NP—000430 / FEBS Lett. 300 (1), 82-88 (1992)
neutrophil gelatinase associated 1 ipocal in/3282 l_at/AI762213/NM_005564/NP 一 005555 /Biochem. Biophys. Res. Commun. 202 (3)， 1468-1475 (1994) neutrophil gelatinase associated 1 ipocal in / 3282 l_at / AI762213 / NM_005564 / NP-005555 / Biochem. Biophys. Res.Commun. 202 (3), 1468-1475 (1994)
==Protease inhibitor== == Protease inhibitor ==
squamous cell carcinoma antigen=serine protease inhibitor/1343— s—at/S6689 6/丽ー 006919/NP— 008850 /Biochem. Biophys. Res. Commun. 181 (1)， 51-58 (199 1) squamous cell carcinoma antigen = serine protease inhibitor / 1343— s—at / S6689 6 / 丽 -006919 / NP—008850 / Biochem. Biophys. Res. Commun. 181 (1), 51-58 (199 1)
squamous cell carcinoma antigen 2 (SCCA2) /1549_s_at/U19557/U19557/AAA9755 3/Proc Natl Acad Sci U S A 1995 Apr 11 ;92 (8) : 3147— 51 squamous cell carcinoma antigen 2 (SCCA2) / 1549_s_at / U19557 / U19557 / AAA9755 3 / Proc Natl Acad Sci USA 1995 Apr 11; 92 (8): 3147-51
tissue inhibitor of metalloproteinases/1693_s_at/D11139/NM_003254/NP_0032 45 /Nature 318 (6041)， 66-69 (1985) tissue inhibitor of metalloproteinases / 1693_s_at / D11139 / NM_003254 / NP_0032 45 / Nature 318 (6041), 66-69 (1985)
mononcyt e/neutrophi 1 elastase inhibitor/33305_at/ 93056/NM_030666/NP_1095 91/Proc. Natl. Acad. Sci. U. S. A. 89 (12) , 5635-5639 (1992) mononcyt e / neutrophi 1 elastase inhibitor / 33305_at / 93056 / NM_030666 / NP_1095 91 / Proc.Natl.Acad.Sci.U.S.A. 89 (12), 5635-5639 (1992)
alpha 1 -antitrypsin /36781一 at/X01683/ M一 000295/NP— 000286 /Proc. Natl. Ac ad. Sci. U. S. A. 78 (11)， 6826-6830 (1981) alpha 1 -antitrypsin / 36781 at / X01683 / M-1000295 / NP—000286 / Proc. Natl. Ac ad. Sci. U.S.A. 78 (11), 6826-6830 (1981)
beta-migrating plasminogen activator inhibitor I /38125_at/M14083/NM_000 602/NP一 000593 /Proc. Natl. Acad. Sci. U. S. A. 83 (18)， 6776 - 6780 (1986) elafin /41469_at/L10343/NM_002638/NP_002629 /Biochem. Biophys. Res. Commu n. 185 (1)， 240-245 (1992) beta-migrating plasminogen activator inhibitor I / 38125_at / M14083 / NM_000 602 / NP-000593 / Proc. Natl. Acad. Sci. USA 83 (18), 6776-6780 (1986) elafin / 41469_at / L10343 / NM_002638 / NP_002629 / Biochem Biophys. Res. Commu n. 185 (1), 240-245 (1992)
==Cytokine, Cytokine Receptor (Growth factorち含む) =  == Cytokine, Cytokine Receptor (including Growth factor) =
interleukin-7 receptor /1370_at/M29696/NM_002185/NP_002176 /Cell 60 (6) ,interleukin-7 receptor / 1370_at / M29696 / NM_002185 / NP_002176 / Cell 60 (6),
941-951 (1990) 941-951 (1990)
IL-13R al/359_at/Y10659/N _001560/NP_001551 /J. Biol. Chem. 271 (46) , 29 265-29270 (1996)  IL-13R al / 359_at / Y10659 / N _001560 / NP_001551 / J. Biol. Chem. 271 (46), 29 265-29270 (1996)
IFN-beta 2a (interleukin 6) /38299_at/X04430/N _000600/ P_000591/Eur. J. B iochem. 159 (3)， 625-632 (1986)  IFN-beta 2a (interleukin 6) /38299_at/X04430/N_000600/P_000591/Eur.J.Biochem. 159 (3), 625-632 (1986)
interleukin 4 receptor/404_at/X52425/NM_000418/ P_000409 /J. Exp. Med. 17 1 (3) , 861-873 (1990) interleukin 4 receptor / 404_at / X52425 / NM_000418 / P_000409 / J. Exp.Med. 17 1 (3), 861-873 (1990)
platelet-derived endothelial cell growth factor /36879_at/M63193/NM_00195 3/NP— 001944 /MoL Cell. Biol. 11 (4)， 2125-2132 (1991) platelet-derived endothelial cell growth factor / 36879_at / M63193 / NM_00195 3 / NP— 001944 / MoL Cell. Biol. 11 (4), 2125-2132 (1991)
pre- B cell enhancing factor (PBEF) /33849_at/U02020/NM_005746/NP_005737 /Mol. Cell. Biol. 14 (2)， 1431—1437 (1994) pre- B cell enhancing factor (PBEF) / 33849_at / U02020 / NM_005746 / NP_005737 / Mol. Cell. Biol. 14 (2), 1431-1437 (1994)
heparin- binding EGF- like growth factor /38037_at/M60278/NM_001945/ P_0019 36 /Biochemistry 32 (31) , 7932-7938 (1993) GM-CSFR beta/37493_at/H04668/N _000395/ P_000386 /Cell 66 (6) , 1165-1174 (1991) heparin-binding EGF- like growth factor / 38037_at / M60278 / NM_001945 / P_0019 36 / Biochemistry 32 (31), 7932-7938 (1993) GM-CSFR beta / 37493_at / H04668 / N _000395 / P_000386 / Cell 66 (6), 1165-1174 (1991)
==Chemokine, Chemokine receptor=  == Chemokine, Chemokine receptor =
interleukin 8 (IL8) /1369—s一 at/M28130/ M一 000584/NP一 000575 /J. Exp. Med. 16 7 (6)， 1883 - 1893 (1988) interleukin 8 (IL8) / 1369-s at / M28130 / M-1000584 / NP-1000575 / J. Exp.Med. 16 7 (6), 1883-1893 (1988)
alternative activated macrophage specific CC chemokine 1 /32128— at/Y1371 0/應ー 002988/NP一 002979 /J. Immunol. 159 (3) , 1140—1149 (1997) alternative activated macrophage specific CC chemokine 1 / 32128— at / Y1371 0 / O-002988 / NP-002979 / J. Immunol. 159 (3), 1140—1149 (1997)
MCP-1/875— g一 at/M26683/ M— 002982/NP一 002973 /FEBS Lett. 244 (2) , 487-493 (1 989) MCP-1 / 875—g-at / M26683 / M—002982 / NP-002973 / FEBS Lett. 244 (2), 487-493 (1 989)
EBIl-ligand chemokine /36067一 at/AB000887/NM一 006274/NP— 006265/JT. Biol. Che m. 272 (21) , 13803-13809 (1997)  EBIl-ligand chemokine / 36067 at / AB000887 / NM-1 006274 / NP— 006265 / JT.Biol. Chem. 272 (21), 13803-13809 (1997)
SLC/36503_at/AB002409/NM_002989/NP_002980/J. Biol. Chem. 272 (31) , 19518 - 19524 (1997)  SLC / 36503_at / AB002409 / NM_002989 / NP_002980 / J. Biol. Chem. 272 (31), 19518-19524 (1997)
lactotransferrin/37149_s_at/U95626/N _002343/NP_002334/Nucleic Acids Res.lactotransferrin / 37149_s_at / U95626 / N _002343 / NP_002334 / Nucleic Acids Res.
18 (13) , 4013 (1990) 18 (13), 4013 (1990)
GR0-beta/37187_at/M36820/N _002089/ P_002080 /Proc. Natl. Acad. Sci. U. S. A. 87 (19)， 7732-7736 (1990) GR0-beta / 37187_at / M36820 / N _002089 / P_002080 / Proc. Natl. Acad. Sci. U.S.A. 87 (19), 7732-7736 (1990)
monocyte chemotactic protein - 2 /37823_at/Y16645/NM_005623/NP_005614 /Bioc hem. Biophys. Res. Commun. 231 (3〉， 726-730 (1997) monocyte chemotactic protein-2 / 37823_at / Y16645 / NM_005623 / NP_005614 / Biochem. Biophys. Res.Commun. 231 (3>, 726-730 (1997)
CCR1/39994一 at/D10925/NM_001295/NP一 001286/Cell 72 (3) , 415-425 (1993) melanoma growth stimulatory activity (MGSA) I Gro alpha/408_at/X54489/ M_ CCR1 / 399994 at / D10925 / NM_001295 / NP 001286 / Cell 72 (3), 415-425 (1993) melanoma growth stimulatory activity (MGSA) I Gro alpha / 408_at / X54489 / M_
001511/NP— 001502 /EMBO J. 7 (7) , 2025-2033 (1988) 001511 / NP— 001502 / EMBO J. 7 (7), 2025-2033 (1988)
==S100 family proteins (small (10-14kDa) calcium binding protein) == psoriasin (S100A7) /34458_at/AA586894/NM_002963/NP_002954/J. Invest. Derma tol. 97 (4) , 701-712 (1991)  == S100 family proteins (small (10-14kDa) calcium binding protein) == psoriasin (S100A7) /34458_at/AA586894/NM_002963/NP_002954/J.Invest.Derma tol. 97 (4), 701-712 (1991)
MRP- 8 (S100A8) /41096_at/AI126134/NM_002964/NP_002955/Nature 330 (6143) , 8 0-82 (1987) MRP- 8 (S100A8) / 41096_at / AI126134 / NM_002964 / NP_002955 / Nature 330 (6143), 8 0-82 (1987)
MRP-14 (S100A9) /41471_at/W72424/ M_002965/NP_002956 /Nature 330 (6143) , 8 0-82 (1987)  MRP-14 (S100A9) / 41471_at / W72424 / M_002965 / NP_002956 / Nature 330 (6143), 80-82 (1987)
CaN19 (S100A2) /2027_at/M87068/NM_005978/NP_005969 /Proc. Natl. Acad. Sci. U. S. A. 90 (14)， 6547-6551 (1993)  CaN19 (S100A2) / 2027_at / M87068 / NM_005978 / NP_005969 / Proc. Natl. Acad. Sci. U.S.A. 90 (14), 6547-6551 (1993)
==Cell adhesion and Related molecule== == Cell adhesion and Related molecule ==
p cadherin /160031一 at/X63629/ML001793/NP一 001784 /J. Cell Biol. 109 (4 Ptp cadherin / 160031-1 at / X63629 / ML001793 / NP-1 001784 / J. Cell Biol. 109 (4 Pt
1) , 1787-1794 (1989) 1), 1787-1794 (1989)
lymph node homing receptor I L-selectin /245_at/M25280/NM_000655/NP_00064 6 /J. Exp. Med. 170 (1) , 123-133 (1989) lymph node homing receptor I L-selectin / 245_at / M25280 / NM_000655 / NP_000646 / J. Exp.Med. 170 (1), 123-133 (1989)
endothelial leukocyte adhesion molecule 1 (ELAM-1) /265_s_at/M24736/NM_000 450/ P_000441/Science 243 (4895)， 1160—1165 (1989) endothelial leukocyte adhesion molecule 1 (ELAM-1) / 265_s_at / M24736 / NM_000 450 / P_000441 / Science 243 (4895), 1160-1165 (1989)
130-kD pemphigus vulgaris antigen / Desmoglein 3/33693_at/M76482/N _00194 4/NP_001935 /Cell 67 (5) , 869-877 (1991)  130-kD pemphigus vulgaris antigen / Desmoglein 3 / 33693_at / M76482 / N _00194 4 / NP_001935 / Cell 67 (5), 869-877 (1991)
leukocyte adhesion protein (LFA - 1/Mac - 1/p 150, 95 family) beta /37918— at/Ml 5395/NM— 000211/NP一 000202/Cell 48 (4)， 681-690 (1987) leukocyte adhesion protein (LFA-1 / Mac-1 / p 150, 95 family) beta / 37918— at / Ml 5395 / NM— 000211 / NP-000202 / Cell 48 (4), 681-690 (1987)
desmocollins type 2b /39302— at/X56807/ M— 004949/NP一 004940/Genomics 10 (3) , 640-645 (1991) desmocollins type 2b / 39302— at / X56807 / M— 004949 / NP-004940 / Genomics 10 (3), 640-645 (1991)
TNFAIP6 (tumor necrosis factor, alpha-induced protein 6)/1372_at/M31165/N M— 007115/NP— 009046 /J. Cell Biol. 116 (2)， 545 - 557 (1992)  TNFAIP6 (tumor necrosis factor, alpha-induced protein 6) / 1372_at / M31165 / N M—007115 / NP—009046 / J. Cell Biol. 116 (2), 545-557 (1992)
==CD antigen, Immunoglobulin - like receptor= == CD antigen, Immunoglobulin-like receptor =
CD24 signal transducer/266_s_at/L33930/NM_013230/NP_037362 /Cancer Res. 5 2 (19)， 5264-5270 (1992)  CD24 signal transducer / 266_s_at / L33930 / NM_013230 / NP_037362 / Cancer Res. 52 (19), 5264-5270 (1992)
M130 antigen extracellular variant I CD163/31438_s_at/Z22971/NM_004244/NP 一 004235 /Eur. J. Immunol. 23 (9)， 2320 - 2325 (1993)  M130 antigen extracellular variant I CD163 / 31438_s_at / Z22971 / NM_004244 / NP-004235 / Eur. J. Immunol. 23 (9), 2320-2325 (1993)
0A3 antigenic surface determinant I CD47/37890一 at/X69398/丽 001777/NP一 001 768 /Cancer Res. 52 (19) , 5416-5420 (1992) 0A3 antigenic surface determinant I CD47 / 37890-at / X69398 / 丽 001777 / NP-001 768 / Cancer Res. 52 (19), 5416-5420 (1992)
CD53 glycoprotein /38378_at/M37033/N _000560/NP_000551 /J. Immunol. 145 (12) , 4322-4325 (1990)  CD53 glycoprotein / 38378_at / M37033 / N _000560 / NP_000551 / J. Immunol. 145 (12), 4322-4325 (1990)
T200 leukocyte common antigen (CD45) isoforml/40518_at/Y00062/ M_002838/ NP一 002829/J. Exp. Med. 166 (5) , 1548—1566 (1987)  T200 leukocyte common antigen (CD45) isoforml / 40518_at / Y00062 / M_002838 / NP-002829 / J. Exp. Med. 166 (5), 1548-1566 (1987)
T200 leukocyte common antigen (CD45) isoform2/40518_at/Y00062/N _080921/ NP一 563578/ J. Exp. Med. 166 (5), 1548 - 1566 (1987)  T200 leukocyte common antigen (CD45) isoform2 / 40518_at / Y00062 / N _080921 / NP-1 563578 / J. Exp.Med. 166 (5), 1548-1566 (1987)
T200 leukocyte common antigen (CD45) isoforra3/40518_at/Y00062/NM_080922/ NP_563579/J. Exp. Med. 166 (5) , 1548 - 1566 (1987)  T200 leukocyte common antigen (CD45) isoforra3 / 40518_at / Y00062 / NM_080922 / NP_563579 / J. Exp.Med. 166 (5), 1548-1566 (1987)
THY- 1 (CD90) /39395_at/AA704137/NI_006288/NP_006279 /Proc Natl Acad Sci U S A 1985 Oct ; 82 (19) :6657-61  THY-1 (CD90) / 39395_at / AA704137 / NI_006288 / NP_006279 / Proc Natl Acad Sci U S A 1985 Oct; 82 (19): 6657-61
monocyte/macrophage Ig— related receptor MIR— 7ノ CD85/35926一 s— at/AF004230/monocyte / macrophage Ig—related receptor MIR— 7 no CD85 / 35926 s—at / AF004230 /
NM— 006669/NP一 006660/Eur J Immunol 1997 Mar ;27 (3) : 660-5 NM—006669 / NP-006660 / Eur J Immunol 1997 Mar; 27 (3): 660-5
leucocyte i画 noglobulin - like receptor - 3 (LIR - 3) /37148_at/AF025533/NM_0leucocyte i painting noglobulin-like receptor-3 (LIR-3) / 37148_at / AF025533 / NM_0
06864/NP一 006855 /J. Immunol. 159 (5)， 2342-2349 (1997) 06864 / NP-1 006855 / J. Immunol. 159 (5), 2342-2349 (1997)
==Extracellular matrix protein==  == Extracellular matrix protein ==
tenascin-C /32818— at/X78565/NM— 002160/NP_002151/J. Biol. Chem. 266 (5) , 2818-2823 (1991) tenascin-C / 32818— at / X78565 / NM— 002160 / NP_002151 / J. Biol. Chem. 266 (5), 2818-2823 (1991)
alpha- 1 type XV collagen /38427_at/L25286/NM_001855/NP_001846 /J Biol Ch em 1994 Feb 18 ;269 (7) : 4773 - 9 alpha- 1 type XV collagen / 38427_at / L25286 / NM_001855 / NP_001846 / J Biol Chem 1994 Feb 18; 269 (7): 4773-9
cartilage oligomeric matrix protein (COMP) /40162_s_at /AC003107/NM_000095 /NP_000086/Genomics 1994 Dec ;24 (3) :435 - 9 cartilage oligomeric matrix protein (COMP) / 40162_s_at / AC003107 / NM_000095 / NP_000086 / Genomics 1994 Dec; 24 (3): 435-9
proteoglycan l/32227_at/X17042/NM_002727/NP_002718 /J. Biol. Chem. 263 (1 5) , 7287-7291 (1988) proteoglycan l / 32227_at / X17042 / NM_002727 / NP_002718 / J.Biol.Chem. 263 (15), 7287-7291 (1988)
"Immunoglobulin, Immunoglobulin receptor, and related molecule= immunoglobulin lambda light chain (constant region) /33273_f_at/X57809/-/~ /配列番号： 3 (塩基配列） 配列番号： 4 (アミノ酸配列） "Immunoglobulin, Immunoglobulin receptor, and related molecule = immunoglobulin lambda light chain (constant region) / 33273_f_at / X57809 /-/ ~ / SEQ ID NO: 3 (base sequence) SEQ ID NO: 4 (amino acid sequence)
Fc-epsi lon-receptor gamma-chain /36889_at/M33195/NM_004106/NP_004097/J B iol Chem 1990 Apr 15 ;265 (11) : 6448-52  Fc-epsi lon-receptor gamma-chain / 36889_at / M33195 / NM_004106 / NP_004097 / J Biol 1990 1990 15; 265 (11): 6448-52
IgG low affinity Fc fragment receptor (CD32) /37688_f_at/M31932/NM_021642 IgG low affinity Fc fragment receptor (CD32) / 37688_f_at / M31932 / NM_021642
/NP_067674/Proc. Natl. Acad. Sci. U. S. A. 85 (7)， 2240 - 2244 (1988) immunoglobulin heavy constant gamma 3 (G3m marker) /37864_s_at/Y14737/-/-Natl. Acad. Sci. U.S.A. 85 (7), 2240-2244 (1988) immunoglobulin heavy constant gamma 3 (G3m marker) / 37864_s_at / Y14737 /-/-/ NP_067674 / Proc.
/配列番号： 5 (塩基配列） 配列番号： 6 (アミノ酸配列） / SEQ ID NO: 5 (base sequence) SEQ ID NO: 6 (amino acid sequence)
immunoglobulin kappa constant /38194_s—at/M63438/ -/-/配列番号： 7 (塩基配 列） 配列番号： 8 (アミノ酸配列） immunoglobulin kappa constant / 38194_s—at / M63438 /-/-/ SEQ ID NO: 7 (base sequence) SEQ ID NO: 8 (amino acid sequence)
—Kinase ana Phosphatase==  —Kinase ana Phosphatase ==
lyn /1402_at/M16038/NM_002350/ P_002341/Mol. Cell. Biol. 7 (1) , 237-243 (1987) lyn / 1402_at / M16038 / NM_002350 / P_002341 / Mol.Cell.Biol. 7 (1), 237-243 (1987)
hemopoietic cell protein - tyrosine kinase (HCK) /2045_s_at/M16592/ M_00211 0/NP_002101 /Mol. Cell. Biol. 7 (6) , 2276-2285 (1987) hemopoietic cell protein-tyrosine kinase (HCK) / 2045_s_at / M16592 / M_00211 0 / NP_002101 /Mol.Cell.Biol. 7 (6), 2276-2285 (1987)
protein tyrosine phosphatase, receptor type, E i sof orml / 32916_at/X54134/protein tyrosine phosphatase, receptor type, Eisoforml / 32916_at / X54134 /
Nl一 006504/NP一 006495 /Oncogene 18 (36)， 5024-5031 (1999) Nl-006504 / NP-006495 / Oncogene 18 (36), 5024-5031 (1999)
protein tyrosine phosphatase, receptor type, E i sof orm2/32916_at/ A J31596protein tyrosine phosphatase, receptor type, Eisoform2 / 32916_at / A J31596
9/蘭一 130435/NP一 569119/Oncogene 18 (36) , 5024-5031 (1999) 9 / Ranichi 130435 / NP-1 569119 / Oncogene 18 (36), 5024-5031 (1999)
KIAA0687 I MAP4K4/35694_at/AB014587/NM_004834/NP_004825/DNA Res. 5 (3) , 1 KIAA0687 I MAP4K4 / 35694_at / AB014587 / NM_004834 / NP_004825 / DNA Res. 5 (3), 1
69-176 (1998) : 69-176 (1998) :
tartrate— resistant acid phosphatase type 5/677_s_at/J04430 /NM一 001611/NP一 001602/ J. Biol. Chem. 264 (1)， 557-563 (1989) tartrate—resistant acid phosphatase type 5 / 677_s_at / J04430 / NM-001611 / NP-001602 / J. Biol. Chem. 264 (1), 557-563 (1989)
==Enzyme (without protease, kinase, phosphatase) == == Enzyme (without protease, kinase, phosphatase) ==
cholesterol 25— hydroxylase/32363— at/AF059214/雇— 003956/NP— 003947 /J. Biol. Chem. 273 (51)， 34316-34327 (1998) cholesterol 25—hydroxylase / 32363—at / AF059214 / employment—003956 / NP—003947 / J. Biol. Chem. 273 (51), 34316-34327 (1998)
Phospholipid scramblase 1/32775— r—at/AB006746/應— 021105/NP— 066928/ J. Biol. Chem. 272 (29) , 18240-18244 (1997) Phospholipid scramblase 1 / 32775— r—at / AB006746 / 應 — 021105 / NP— 066928 / J. Biol. Chem. 272 (29), 18240-18244 (1997)
manganese superoxide dismutase (EC 1. 15. 1. 1) /34666_at/X07834/NM_000636/N P一 000627 /FEBS Lett. 229 (2) , 256—260 (1988) manganese superoxide dismutase (EC 1.15.1.1) / 34666_at / X07834 / NM_000636 / NP-1000627 / FEBS Lett. 229 (2), 256-260 (1988)
ornithine decarboxylase ODC (EC 4. 1. 1. 17) /36203_at/X16277/NM_002539/NP_0 02530 /DNA 6 (3) , 179-187 (1987) ornithine decarboxylase ODC (EC 4.1.1.17) / 36203_at / X16277 / NM_002539 / NP_0 02530 / DNA 6 (3), 179-187 (1987)
phospholipase A2, group IIA (platelets, synovial fluid) /37017_at/M22430/N M_000300/NP_000291/J. Biol. Chem. 264 (10) , 5335-5338 (1989) phospholipase A2, group IIA (platelets, synovial fluid) / 37017_at / M22430 / N M_000300 / NP_000291 / J. Biol. Chem. 264 (10), 5335-5338 (1989)
nicotinamide N-methyltransferase (N 1T) /37032—at/U08021/ M— 006169/NP— 006 160/X Biol. Chem. 269 (20) , 14835-14840 (1994) nicotinamide N-methyltransferase (N 1T) / 37032—at / U08021 / M— 006169 / NP— 006 160 / X Biol. Chem. 269 (20), 14835-14840 (1994)
uridine phosphorylase /37351一 at/X90858/NM一 003364/NP一 003355 /Biochera. Bio phys. Res. Conunun. 216 (1) , 265-272 (1995) uridine phosphorylase / 37351 at / X90858 / NM-1003364 / NP-1003355 / Biochera.Biophys.Res.Conunun.216 (1), 265-272 (1995)
aldose reductase - like peptide /37482— at/U37100/ M— 020299/NP—064695/配列番 号： 9 (塩基配列） 配列番号： 1 0 (アミノ酸配列） aldose reductase-like peptide / 37482— at / U37100 / M—020299 / NP—064695 / SEQ ID NO: 9 (base sequence) SEQ ID NO: 10 (amino acid sequence)
2，， 5， oligoadenylate synthetase isoform E16/38389_at/X04371/N¾L002534/NP_ 002525/EMBO J. 4 (9)， 2249-2256 (1985)  2 ,, 5, oligoadenylate synthetase isoform E16 / 38389_at / X04371 / N¾L002534 / NP_ 002525 / EMBO J. 4 (9), 2249-2256 (1985)
2，， 5' oligoadenylate synthetase isoform E18/38389_at/X02875/NM_016816/NP_ 058132/EMBO J. 4 (9)， 2249-2256 (1985)  2 ,, 5 'oligoadenylate synthetase isoform E18 / 38389_at / X02875 / NM_016816 / NP_ 058132 / EMBO J. 4 (9), 2249-2256 (1985)
2'， 5' oligoadenylate synthetase 2 isoform p69/39263_at/M87284/NM_002535/ NP一 002526/J Biol Chem 1992 May 15 ;267 (14) :9933— 9  2 ', 5' oligoadenylate synthetase 2 isoform p69 / 39263_at / M87284 / NM_002535 / NP-002526 / J Biol Chem 1992 May 15; 267 (14): 9933— 9
2，， 5' oligoadenylate synthetase 2 isoform p71/39263_at/M87434/NM_016817/ NP— 058197/J Biol Chem 1992 May 15 ;267 (14) :9933 - 9  2 ,, 5 'oligoadenylate synthetase 2 isoform p71 / 39263_at / M87434 / NM_016817 / NP— 058197 / J Biol Chem 1992 May 15; 267 (14): 9933-9
L-kynurenine ydrolase/40671_g_at/AI148772/NM_003937/NP_003928 /Eur. J. B iochem. 239 (2) , 460-468 (1996)  L-kynurenine ydrolase / 40671_g_at / AI148772 / NM_003937 / NP_003928 / Eur.J.Biochem.239 (2), 460-468 (1996)
purine nucleoside phosphorylase (PNP ; EC 2. 4. 2. 1) /430一 at/X00737 /匪一 000270 /NP— 000261/J. Biol. Chem. 262 (5) , 2332-2338 (1987) purine nucleoside phosphorylase (PNP; EC 2.4.2.2.1) / 430-at / X00737 / marauder 000270 / NP— 000261 / J. Biol. Chem. 262 (5), 2332-2338 (1987)
2' , 5' oligoadenylate synthetase - like (59 kDa isoform) /34491_at/AJ225089 / M_003733/ P_003724/Nucleic Acids Res. 26 (18)， 4121-4128 (1998) 2 ', 5' oligoadenylate synthetase-like (59 kDa isoform) / 34491_at / AJ225089 / M_003733 / P_003724 / Nucleic Acids Res. 26 (18), 4121-4128 (1998)
==Cytoskeletal structural protein, cytoskeleton associated protein== cytokeratin 17 /34301— r— at/Z19574/NM— 000422/NP— 000413/Eur J Cell Biol 199== Cytoskeletal structural protein, cytoskeleton associated protein == cytokeratin 17 / 34301—r—at / Z19574 / NM—000422 / NP—000413 / Eur J Cell Biol 199
2 Oct ; 59 (1)： 127-37 2 Oct; 59 (1): 127-37
keratin 6A/39015_f_at/L42611/M_005554/NP_005545/J. Biol. Chem. 270 (31) , 18581-18592 (1995) keratin 6A / 39015_f_at / L42611 / M_005554 / NP_005545 / J.Biol.Chem. 270 (31), 18581-18592 (1995)
keratin 16/37473_at/AF061812/NM_005557/NP_005548 /Mol. Cell. Biol. 8 (2)， 722-736 (1988) keratin 16 / 37473_at / AF061812 / NM_005557 / NP_005548 / Mol. Cell. Biol. 8 (2), 722-736 (1988)
actin related protein 2/3 complex, subunit IB (41 kD) /39043_at/AF006084/N M_005720/NP_005711 /J Cell Biol 1997 Jul 28； 138 (2) :375-84 actin related protein 2/3 complex, subunit IB (41 kD) / 39043_at / AF006084 / N M_005720 / NP_005711 / J Cell Biol 1997 Jul 28; 138 (2): 375-84
myosin VA (heavy polypeptide 12, myoxin) /40571_at/U90942/NM_000259/NP_000 250/Genomics 19 (3) , 407-416 (1994) myosin VA (heavy polypeptide 12, myoxin) / 40571_at / U90942 / NM_000259 / NP_000 250 / Genomics 19 (3), 407-416 (1994)
Small proline- rich protein SPRK/33546_at/AI923984/S73288/-/Arch. Oral Bio 1. 39 (3) , 251-259 (1994)  Small proline-rich protein SPRK / 33546_at / AI923984 / S73288 /-/ Arch.Oral Bio 1.39 (3), 251-259 (1994)
small proline- rich protein 2A/36734_at/M21302/ _005988/ P_005979/Genomic s 16 (3) , 630-637 (1993) small proline-rich protein 2A / 36734_at / M21302 / _005988 / P_005979 / Genomics 16 (3), 630-637 (1993)
small proline- rich protein IB (cornif in) /37160_at/M19888/NM_003125/NP_003 116/Genomics 16 (3) , 630-637 (1993) small proline-rich protein IB (cornif in) / 37160_at / M19888 / NM_003125 / NP_003 116 / Genomics 16 (3), 630-637 (1993)
involucrin /36355_at/M13903/NM_005547/NP_005538 /Cell 1986 Aug 15 ;46 (4)： 583-9 : involucrin / 36355_at / M13903 / NM_005547 / NP_005538 / Cell 1986 Aug 15; 46 (4): 583-9:
myosin IB/41439_at/AJ001381/NM_012223/ P_036355/Proc. Natl. Acad. Sci. U. S. A. 91 (14) , 6549-6553 (1994) myosin IB / 41439_at / AJ001381 / NM_012223 / P_036355 / Proc. Natl. Acad. Sci. U.S.A. 91 (14), 6549-6553 (1994)
==Int erf eron-induci D 1 e protein== == Int erf eron-induci D 1 e protein ==
interferon-inducible protein p78 (MX1 ) /37014_at/M33882/NM_002462/NP_00245interferon-inducible protein p78 (MX1) / 37014_at / M33882 / NM_002462 / NP_00245
3 /Mol. Cell. Biol. 9 (11) , 5062-5072 (1989) 3 / Mol. Cell. Biol. 9 (11), 5062-5072 (1989)
ga腕 a- interferon- inducible protein (IP- 30) /39728_at/J03909/NM_006332/NP —006323 /J Biol Chem 1988 Aug 25 ;263 (24) : 12036-43 ga arm a- interferon- inducible protein (IP-30) / 39728_at / J03909 / NM_006332 / NP —006323 / J Biol Chem 1988 Aug 25; 263 (24): 12036-43
interferon- induced 17- kDa/15— kDa protein/1107_s_at/M13755/NM_005101/NP_00 5092 /J Biol Chem 1986 Jul 5 ;261 (19) : 8811-6 interferon- induced 17- kDa / 15- kDa protein / 1107_s_at / M13755 / NM_005101 / NP_00 5092 / J Biol Chem 1986 Jul 5; 261 (19): 8811-6
p27, interferon-alpha-inducible protein 27/425_at/X67325/NM_005532/NP_005 523 /Cancer Res 1993 Sep 1； 53 (17) :4096-101 p27, interferon-alpha-inducible protein 27 / 425_at / X67325 / NM_005532 / NP_005 523 / Cancer Res 1993 Sep 1; 53 (17): 4096-101
==G-protein and related molecule= == G-protein and related molecule =
RAB31/33371— s一 at/U59877/NM— 006868/ P— 006859/Gene 174 (1), 129-134 (1996) regulator of G - protein signalling 1 (BL34) /36575_at/S59049/ M_002922/NP —002913/J Immunol 1993 May 1 ; 150 (9) : 3895-904  RAB31 / 33371—s-at / U59877 / NM—006868 / P—006859 / Gene 174 (1), 129-134 (1996) regulator of G-protein signaling 1 (BL34) / 36575_at / S59049 / M_002922 / NP —002913 / J Immunol 1993 May 1; 150 (9): 3895-904
regulator of G- protein signalling 20/41086_at/AF060877/NM_003702/ P_00369 3 /J. Biol. Chem. 273 (40) , 26014-26025 (1998) regulator of G- protein signaling 20 / 41086_at / AF060877 / NM_003702 / P_003693 / J. Biol. Chem. 273 (40), 26014-26025 (1998)
==Transcription factor= == Transcription factor =
STATl/33339_g_at/M97936/NM_007315/NP_009330/Proc Natl Acad Sci U S A 1992 Aug 15 ;89 (16) : 7836-9  STATl / 33339_g_at / M97936 / NM_007315 / NP_009330 / Proc Natl Acad Sci U S A 1992 Aug 15; 89 (16): 7836-9
TNRC3/41246_at/AI743134/N¾L005878/NP_005869/Hura. Genet. 100 (1) , 114-122 TNRC3 / 41246_at / AI743134 / N¾L005878 / NP_005869 / Hura.Genet. 100 (1), 114-122
(1997) (1997)
==0thers=  == 0thers =
insulin-like growth factor binding protein 4 (IGFBP4) /1737_s_at/M62403/NM — 001552/ P— 001543 /Mol. Endocrinol. (10) , 1451-1458 (1990) insulin-like growth factor binding protein 4 (IGFBP4) / 1737_s_at / M62403 / NM — 001552 / P— 001543 / Mol. Endocrinol. (10), 1451-1458 (1990)
cyclin B/1945_at/M25753/NM_031966/NP_l 14172 /Cell 58 (5) , 833-846 (1989) proto- oncogene (Wnt~5a) /31862_at/L20861/NM_003392/NP_003383/Genomics 199 3 Nov ; 18 (2) :249-60 cyclin B / 1945_at / M25753 / NM_031966 / NP_l 14172 / Cell 58 (5), 833-846 (1989) proto-oncogene (Wnt ~ 5a) / 31862_at / L20861 / NM_003392 / NP_003383 / Genomics 1993 Nov; 18 (2) : 249-60
beta defensin 2 (HBD2) /32464_at/AF071216/NM_004942/ P_004933/Nature 387 (6636) , 861 (1997) beta defensin 2 (HBD2) / 32464_at / AF071216 / NM_004942 / P_004933 / Nature 387 (6636), 861 (1997)
ne related protein 2 /32598_at/D83018/匪— 006159/NP— 006150/Genomics 38 (3) , 273-276 (1996) neuronal tissue-enriched acidic protein (NAP- 22) /32607_at/AF039656/NM_0 06317/NP_006308 /Mol Cells 1998 Aug 31 ;8 (4) :471-7 ne related protein 2 / 32598_at / D83018 / marauder— 006159 / NP— 006150 / Genomics 38 (3), 273-276 (1996) neuronal tissue-enriched acidic protein (NAP-22) / 32607_at / AF039656 / NM_0 06317 / NP_006308 / Mol Cells 1998 Aug 31; 8 (4): 471-7
DKFZp58600118 / KIAA1199 /36070_at/AL049389/AB033025/CAB94391/DNA Res. 6 (5) , 337-345 (1999)  DKFZp58600118 / KIAA1199 / 36070_at / AL049389 / AB033025 / CAB94391 / DNA Res. 6 (5), 337-345 (1999)
丄 ysosomal - associated mult i transmembrane protein (LAPTm5) /37759_at/U51240 /NM—006762/NP— 006753 /Genomics 35 (2) , 328-337 (1996) 丄 ysosomal-associated mult i transmembrane protein (LAPTm5) / 37759_at / U51240 / NM—006762 / NP—006753 / Genomics 35 (2), 328-337 (1996)
KIAA0101 /38116_at/D14657/NM_014736/ P_055551/DNA Res. 2 (1) , 37-43 (199 5)  KIAA0101 / 38116_at / D14657 / NM_014736 / P_055551 / DNA Res. 2 (1), 37-43 (199 5)
KIAA0296/39862— at/M528252/NM— 014699/ P_055514/配列番号： 1 1 (塩基配列） 配列番号： 1 2 (アミノ酸配列）  KIAA0296 / 39862—at / M528252 / NM—014699 / P_055514 / SEQ ID NO: 11 (base sequence) SEQ ID NO: 12 (amino acid sequence)
serum amyloid A1/33272一 at/ 829286/NM— 000331/NP一 000322/J. Clin. Invest. 8 2 (5) , 1670-1675 (1988) serum amyloid A1 / 33272 at / 829286 / NM— 000331 / NP 000322 / J. Clin. Invest. 8 2 (5), 1670-1675 (1988)
tumor suppressing subtransferable candidate 3 (TSSC3) /31888_s_at/AF001294 /NM一 003311/NP一 003302/Hum Mol Genet 1997 Nov;6 (12) :2021-9 tumor suppressing subtransferable candidate 3 (TSSC3) / 31888_s_at / AF001294 / NM-003311 / NP-003302 / Hum Mol Genet 1997 Nov; 6 (12): 2021-9
TYRO protein tyrosine kinase binding protein/38363_at/W60864/NM_003332/NP —003323/Nature 1998 Feb 12 ;391 (6668) : 703-7 TYRO protein tyrosine kinase binding protein / 38363_at / W60864 / NM_003332 / NP —003323 / Nature 1998 Feb 12; 391 (6668): 703-7
fatty acid binding protein homologue (PA-FABP) /39799_at/M94856/ M_00144 4/NP一 001435 /J. Invest. Dermatol. 99 (3) , 299-305 (1992) fatty acid binding protein homologue (PA-FABP) / 39799_at / M94856 / M_00144 4 / NP-001435 /J.Invest.Dermatol. 99 (3), 299-305 (1992)
heparin binding protein (HBpl7) / FGF- BPl/38489— at/M60047/ l—005130/NP— 00 5121 /J Biol Chem 1991 Sep 5 ;266 (25) : 16778-85 heparin binding protein (HBpl7) / FGF-BPl / 38489— at / M60047 / l—005130 / NP— 00 5121 / J Biol Chem 1991 Sep 5; 266 (25): 16778-85
transcobalamin I /35919_at/J05068/ M_001062/NP_001053 /J Biol Chem 1989 Sep 25 ; 264 (27) : 15754—7 transcobalamin I / 35919_at / J05068 / M_001062 / NP_001053 / J Biol Chem 1989 Sep 25; 264 (27): 15754-7
fibrinogen— like 2/39591— s— at/ Z36531/ _006682/NP_006673/Gene 160 (2) , 25 ト 262 (1995) preferentially expressed in memory T lymphocytes and at low levels or not at all in naive T lymphocytes. fibrinogen— like 2 / 39591— s— at / Z36531 / _006682 / NP_006673 / Gene 160 (2), 25 262 (1995) preferentially expressed in memory T lymphocytes and at low levels or not at all in naive T lymphocytes.
six transmembrane epithelial antigen of the prostate (STEAP) /40297_at/AC0 1 5 5し ― —一」 six transmembrane epithelial antigen of the prostate (STEAP) / 40297_at / AC0 1 5 5 do-one
05053/NM_012449/NP_036581/Proc. Natl. Acad. Sci. U. S. A. 96 (25) , 14523-14 528 (1999)  05053 / NM_012449 / NP_036581 / Proc.Natl.Acad.Sci.U.S.A. 96 (25), 14523-14 528 (1999)
—データ 2 —Data 2
(アトピー性皮膚炎患者の皮疹部における発現レベルが、 同一の患者の無疹部 に比べて低い指標遺伝子群）  (Indicator genes whose expression level in the rash area of patients with atopic dermatitis is lower than that in the rash area of the same patient)
==Protease== == Protease ==
kallikrein l/246_at/M25629/M_002257/NP_002248 /Biochemistry 1985 Dec 31 ; 24(27) : 8037-43 kallikrein l / 246_at / M25629 / M_002257 / NP_002248 / Biochemistry 1985 Dec 31; 24 (27): 8037-43
cathepsin V /40717_at/AB001928/NM_001333/ P_001324 /Invest Ophthalmol Vis Sci 1998 Sep ; 39 (10) : 1789 - 96 cathepsin V / 40717_at / AB001928 / NM_001333 / P_001324 / Invest Ophthalmol Vis Sci 1998 Sep; 39 (10): 1789-96
==Protease inhibitor= == Protease inhibitor =
cystatin E/M/33128_s_at/W68521/ _001323/NP_001314 /J. Biol. Chem. 272 (2) , 903-910 (1997) cystatin E / M / 33128_s_at / W68521 / _001323 / NP_001314 / J. Biol. Chem. 272 (2), 903-910 (1997)
SERPINB7 (serine (or cysteine) proteinase inhibitor, clade B (ovalbumin) , member 7) /35577_at/AF027866/NM_003784/NP_003775/J. Biol. Chem. 272 (24) , 15373-15380 (1997)  SERPINB7 (serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 7) / 35577_at / AF027866 / NM_003784 / NP_003775 / J. Biol. Chem. 272 (24), 15373-15380 (1997)
tissue inhibitor of metal loproteinase 4 /819_at/U76456/NM_003256/ P_00324 7 /J Biol Chem 1996 Nov 29 ;271 (48) : 30375 - 80 tissue inhibitor of metal loproteinase 4 / 819_at / U76456 / NM_003256 / P_00324 7 / J Biol Chem 1996 Nov 29; 271 (48): 30375-80
==Cell adhesion and related mo丄 ecule== == Cell adhesion and related mo 丄 ecule ==
KIAA1775 (MT-protocadherin) /37857_at/AL080188/NM_033100/NP_149091/Brain R es Mol Brain Res 2001 Oct 19 ; 94 (1-2) :85-95  KIAA1775 (MT-protocadherin) / 37857_at / AL080188 / NM_033100 / NP_149091 / Brain Res Mol Brain Res 2001 Oct 19; 94 (1-2): 85-95
==Cytoskeletal structural protein, cytoskeleton associated protein== keratin 18 /35766_at/M26326/NM_000224/NP_000215 /Differentiation 33 (1)， 61-68 (1986)  == Cytoskeletal structural protein, cytoskeleton associated protein == keratin 18 / 35766_at / M26326 / NM_000224 / NP_000215 / Differentiation 33 (1), 61-68 (1986)
cytokeratin 15 /37582_at/X07696/NM_002275/NP_002266 /J. Cell Biol. 106 (4) , 1249-1261 (1988) cytokeratin 15 / 37582_at / X07696 / NM_002275 / NP_002266 / J.Cell Biol. 106 (4), 1249-1261 (1988)
keratin 19 /40899_at/Y00503/N _002276/ P_002267 /Nucleic Acids Res. 15 (2 3 10058 (1987) keratin 19 / 40899_at / Y00503 / N _002276 / P_002267 / Nucleic Acids Res. 15 (2 3 10058 (1987)
smooth muscle myosin heavy chain 11, isoform SM2 /37407_s_at/AF013570/NM_ 022844/NP_074035/Am. J. Med. Genet. 46 (1 61—67 (1993) smooth muscle myosin heavy chain 11, isoform SM2 / 37407_s_at / AF013570 / NM_022844 / NP_074035 / Am.J.Med.Genet. 46 (1 61—67 (1993)
sciellin (SCEL) /35105_at/AF045941/NM_003843/NP_003834/ J. Biol. Chem. 273 (47) , 31547-31554 (1998) sciellin (SCEL) / 35105_at / AF045941 / NM_003843 / NP_003834 / J. Biol. Chem. 273 (47), 31547-31554 (1998)
KIM0353 I desmuslin (intermediate filament protein) /39544_at/AB002351/AF 359284/AAK57487/Proc. Natl. Acad. Sci. U. S. A. 98 (11) , 6156 - 6161 (2001) calponin 1 /34203_at/D17408/ i_001299/NP_001290/Biochem Biophys Res Co n 1995 Dec 5 ;217 (1) : 238— 44  KIM0353 I desmuslin (intermediate filament protein) / 39544_at / AB002351 / AF 359284 / AAK57487 / Proc.Natl.Acad.Sci. Biophys Res Con 1995 Dec 5; 217 (1): 238—44
desmin /40776_at/ 63391/N _001927/NP_001918/Gene 78 (2 243-254 (1989) ==Extracellular matrix protein= desmin / 40776_at / 63391 / N _001927 / NP_001918 / Gene 78 (2 243-254 (1989) == Extracellular matrix protein =
extracellular matrix protein 2/39673_i_at/AB011792/ ¾L001393/NP_001384/Ge nomics 1998 Sep 15 ;52 (3) : 378-81 extracellular matrix protein 2 / 39673_i_at / AB011792 / ¾L001393 / NP_001384 / Ge nomics 1998 Sep 15; 52 (3): 378-81
==Kinase and Phosphatase:- protein- tyrosine- phosphatase Dl /40524_at/X79510/NM_007039/ P_008970/Proc Natl Acad Sci U S A 1994 Aug 2 ;91 (16) : 7477-81 == Kinase and Phosphatase:-protein- tyrosine- phosphatase Dl / 40524_at / X79510 / NM_007039 / P_008970 / Proc Natl Acad Sci U S A 1994 Aug 2; 91 (16): 7477-81
KI 0537 /33787_at/AB011109/NM_014840/NP_055655/DNA Res. 5 (1) , 31—39 (19 98) '  KI 0537 / 33787_at / AB011109 / NM_014840 / NP_055655 / DNA Res. 5 (1), 31-39 (19 98) ''
==Enzyme (without protease, kinase, phosphatase and alcohol dehydrogenas e)=  == Enzyme (without protease, kinase, phosphatase and alcohol dehydrogenas e) =
angiogenin (RNase A family, 5) /1103— at/M11567/丽— 001145/NP— 001136/Bioch emistry 24 (20) , 5494-5499 (1985) angiogenin (RNase A family, 5) / 1103— at / M11567 / 丽 — 001145 / NP— 001136 / Bioch emistry 24 (20), 5494-5499 (1985)
RNase 4 /32664_at/D37931/NM_002937/NP_002928 /Biochim. Biophys. Acta 1261 (3 424-426 (1995) deoxyribonuclease I一 like 2 (DNAS1L2) /31704_at/U62647/NM_001374/NP_001365 /Genomics 42 (3) , 507-513 (1997) RNase 4 /32664_at/D37931/NM_002937/NP_002928/Biochim.Biophys.Acta 1261 (3 424-426 (1995) deoxyribonuclease I-like 2 (DNAS1L2) / 31704_at / U62647 / NM_001374 / NP_001365 / Genomics 42 (3), 507-513 (1997)
phosphoenolpyruvate carboxykinase (PCK1) /33702_f_at/L05144/NM_002591/ P 一 002582/Genomics 16 (3) , 698—706 (1993) phosphoenolpyruvate carboxykinase (PCK1) / 33702_f_at / L05144 / NM_002591 / P-00250025 / Genomics 16 (3), 698-706 (1993)
carbonic anhydrase isozyme VI (CA6) /35051_at/M57892/NM_001215/NP_001206 /Biochemistry 30 (2) , 569-575 (1991) carbonic anhydrase isozyme VI (CA6) / 35051_at / M57892 / NM_001215 / NP_001206 / Biochemistry 30 (2), 569-575 (1991)
3-hydroxy-3-methylglutaryl coenzyme A synthase/35345_at/X83618/N¾L005518/ NP_005509/Arch. Biochem. Biophys. 317 (2) , 385-390 (1995)  3-hydroxy-3-methylglutaryl coenzyme A synthase / 35345_at / X83618 / N¾L005518 / NP_005509 / Arch.Biochem.Biophys. 317 (2), 385-390 (1995)
arylacetamide deacetylase /36512—at/L32179/NM— 001086/NP— 001077/J. Biol. C hem. 269 (34) , 21650-21656 (1994) arylacetamide deacetylase / 36512—at / L32179 / NM— 001086 / NP— 001077 / J. Biol. Chem. 269 (34), 21650-21656 (1994)
ATPase, Cu++ transporting, alpha polypeptide (ATP7A) /36523_at/L06133/N _0 00052/NP— 000043/Nat. Genet. 3 (1) , 7—13 (1993)  ATPase, Cu ++ transporting, alpha polypeptide (ATP7A) / 36523_at / L06133 / N _0 00052 / NP— 000043 / Nat. Genet. 3 (1), 7-13 (1993)
tyrosinase (TYR) ノ 38927— i_at/M27160/N—000372/NP— 000363/Proc. Natl. Acad.tyrosinase (TYR) no 38927— i_at / M27160 / N—000372 / NP— 000363 / Proc. Natl. Acad.
Sci. U. S. A. 84 (21) , 7473-7477 (1987) Sci.U.S.A. 84 (21), 7473-7477 (1987)
amylase, alpha 2B; pancreatic/36680_at/M24895/NM_020978/NP_066188/Gene 90amylase, alpha 2B; pancreatic / 36680_at / M24895 / NM_020978 / NP_066188 / Gene 90
(2)， 281-286 (1990) (2), 281-286 (1990)
CMP-N-acetylneuraminic acid hydroxylase /39317— at/D86324/NM— 003570/NP— 00 3561/J. Biol. Chem. 270 (27) , 16458—16463 (1995)  CMP-N-acetylneuraminic acid hydroxylase / 39317— at / D86324 / NM— 003570 / NP— 00 3561 / J. Biol. Chem. 270 (27), 16458—16463 (1995)
Aminomethyltransf erase (glycine cleavage system protein T) /41120_at/D1468 6/NM— 000481/NP— 000472/J Biol Chem 1991 Feb 15 ; 266 (5) : 3323-9  Aminomethyltransf erase (glycine cleavage system protein T) / 41120_at / D1468 6 / NM— 000481 / NP— 0000472 / J Biol Chem 1991 Feb 15; 266 (5): 3323-9
monoamine oxidase A/41771_g_at/AA420624/ M_000240/NP_000231/Proc. Natl. A cad. Sci. U. S. A. 85 (13) , 4934—4938 (1988) monoamine oxidase A / 41771_g_at / AA420624 / M_000240 / NP_000231 / Proc. Natl. A cad. Sci. U.S.A. 85 (13), 4934-4938 (1988)
Aldehyde dehydrogenase 5 family, member Al/41790_at/AL031230/ M_001080/NP —001071/J. Biol. Chem. 270 (1) , 461-467 (1995)  Aldehyde dehydrogenase 5 family, member Al / 41790_at / AL031230 / M_001080 / NP —001071 / J. Biol. Chem. 270 (1), 461-467 (1995)
CYTOCHROME P450, SUBFAMILY IIIA, POLYPEPTIDE 5/37124—i— at/J04813 /匪一 00077 7/NP— 000768/JT. Biol. Chem. 264 (18) , 10388-10395 (1989) ==Alcohol dehydrogenase- alcohol dehydrogenase 1A (class I) , alpha polypeptide/34637— f一 at/M12963/N M_000667/NP_000658 /Proc. Natl. Acad. Sci. U. S. A. 83 (3) , 634-638 (1986) alcohol dehydrogenase IB (class I) , beta polypeptide/35730_at/X03350/NM_0 00668/NP— 000659/Proc Natl Acad Sci U S A 1986 Feb ;83 (3) : 634-8 CYTOCHROME P450, SUBFAMILY IIIA, POLYPEPTIDE 5 / 37124—i—at / J04813 / Martian 1 00077 7 / NP—000768 / JT.Biol. == Alcohol dehydrogenase- alcohol dehydrogenase 1A (class I), alpha polypeptide / 34637- f-at / M12963 / N M_000667 / NP_000658 / Proc. Natl. Acad.Sci. USA 83 (3), 634-638 (1986) alcohol dehydrogenase IB (class I), beta polypeptide / 35730_at / X03350 / NM_0 00668 / NP—000659 / Proc Natl Acad Sci USA 1986 Feb; 83 (3): 634-8
alcohol dehydrogenase 1C (class I) , gamma polypeptide/36247_f_at/M12272/N M— 000669/NP— 000660/Proc Natl Acad Sci U S A 1986 Feb ;83 (3) : 634-8 alcohol dehydrogenase 1C (class I), gamma polypeptide / 36247_f_at / M12272 / N M- 000669 / NP- 000660 / Proc Natl Acad Sci U S A 1986 Feb; 83 (3): 634-8
==Fatty acid metabolism == == Fatty acid metabolism ==
degenerative spermatocyte homo log (sphingolipid delta 4 desaturase) /33337 _at/AF002668/ L003676/NP_003667 /Biochemistry 36 (23)， 6960-6967 (1997) FABP7 (fatty acid binding protein 7) /35185_at/AJ002962/NM_001446/NP_0014 37/Biochim. Biophys. Acta 1354 (1) , 24-28 (1997) degenerative spermatocyte homo log (sphingolipid delta 4 desaturase) / 33337 _at / AF002668 / L003676 / NP_003667 / Biochemistry 36 (23), 6960-6967 (1997) FABP7 (fatty acid binding protein 7) / 35185_at / AJ002962 / NM_001446 / NP_0014 37 / Biochim. Biophys. Acta 1354 (1), 24-28 (1997)
alpha- 2- glycoprotein 1， zinc/35834_at/X59766/NM_001185/NP_001176/Biochem.alpha-2-glycoprotein 1, zinc / 35834_at / X59766 / NM_001185 / NP_001176 / Biochem.
Biophys. Res. Commun. 177 (2) , 696-703 (1991) Biophys. Res. Commun. 177 (2), 696-703 (1991)
perilipin /37122— at/AB005293/ M— 002666/ P— 002657/Genomics 48 (2)， 254-257perilipin / 37122— at / AB005293 / M— 002666 / P— 002657 / Genomics 48 (2), 254-257
(1998) (1998)
FABP4 (Fatty acid binding protein 4) /38430_at/AA128249/NM_001442/NP_00143 3/Biochemistry 28 (22)， 8683—8690 (1989)  FABP4 (Fatty acid binding protein 4) / 38430_at / AA128249 / NM_001442 / NP_001433 / Biochemistry 28 (22), 8683-8860 (1989)
lipoprotein lipase /41209— at /Ml 5856/NM—000237/NP— 000228 /Science 235 (479 6) , 1638-1641 (1987) lipoprotein lipase / 41209—at / Ml 5856 / NM—000237 / NP—000228 / Science 235 (479 6), 1638-1641 (1987)
aldehyde dehydrogenase 3 family, member A2/40409_at/U46689/NM_000382/ P_0 00373 /Nat. Genet. 12 (1)， 52-57 (1996) aldehyde dehydrogenase 3 family, member A2 / 40409_at / U46689 / NM_000382 / P_0 00373 / Nat. Genet. 12 (1), 52-57 (1996)
phytanoyl-CoA hydroxylase interacting protein (KIAA0273) /37191_at/D87463/ 匪— 014759/NP— 055574/DNA Res. 3 (5) , 321-329 (1996) phytanoyl-CoA hydroxylase interacting protein (KIAA0273) / 37191_at / D87463 / Marauder— 014759 / NP— 055574 / DNA Res. 3 (5), 321-329 (1996)
~Apolipoprotein==  ~ Apolipoprotein ==
apolipoprotein D /36681一 at/J02611/NM— 001647/NP— 001638/J. Biol. Chem. 261 (35) , 16535-16539 (1986) apolipoprotein D / 36681 at / J02611 / NM— 001647 / NP— 001638 / J. Biol. Chem. 261 (35), 16535-16539 (1986)
apolipoprotein E/608_at/M12529/NM_000041/NP_000032/J. Biol. Chem. 257 (2apolipoprotein E / 608_at / M12529 / NM_000041 / NP_000032 / J. Biol. Chem. 257 (2
4) , 14639-14641 (1982) 4), 14639-14641 (1982)
==Grobin=  == Grobin =
Hemoglobin alpha 1 chain (HBAl) /31525_s_at/J00153/NM_000558/NP_000549/Na ture 290 (5801)， 26-29 (1981)  Hemoglobin alpha 1 chain (HBAl) / 31525_s_at / J00153 / NM_000558 / NP_000549 / Nature 290 (5801), 26-29 (1981)
Hemoglobin alpha 2 chain (HBA2) /31525_s_at/J00153/NM_000517/NP_000508 /N ature 290 (5801) , 26—29 (1981)  Hemoglobin alpha 2 chain (HBA2) / 31525_s_at / J00153 / NM_000517 / NP_000508 / Nature 290 (5801), 26-29 (1981)
hemoglobin, gamma A (HBGl) /38585_at/M91036/NM_000559/NP_000550/Cell 21 (3) , 627-638 (1980) hemoglobin, gamma A (HBGl) / 38585_at / M91036 / NM_000559 / NP_000550 / Cell 21 (3), 627-638 (1980)
hemoglobin, gamma G (HBG2) /38585_at/M91036/NM_000184/ P_000175/Cell 21 (3)， 627-638 (1980) hemoglobin, gamma G (HBG2) / 38585_at / M91036 / NM_000184 / P_000175 / Cell 21 (3), 627-638 (1980)
hemoglobin, beta/31687_f_at/M25079/NM_000518/NP_000509 /Prog. Nucleic Aci d Res. Mol. Biol. 19， 165-175 (1976) hemoglobin, beta / 31687_f_at / M25079 / NM_000518 / NP_000509 / Prog.Nucleic Acid Res. Mol. Biol. 19, 165-175 (1976)
ma画 aglobin l/36329_at/U33147/NM_002411/NP_002402 /Cancer Res. 56 (4) , 86 0-865 (1996) ma painting aglobin l / 36329_at / U33147 / NM_002411 / NP_002402 / Cancer Res. 56 (4), 86 0-865 (1996)
raa賺 aglobin 2 /41066_at/AF071219/NM_002407/NP_002398/Genoraics 54 (1)， 70- 78 (1998) raa stock aglobin 2 / 41066_at / AF071219 / NM_002407 / NP_002398 / Genoraics 54 (1), 70-78 (1998)
secretoglobin, family ID, member 2/32880— at/AW015055/ M一 006551/ P一 006542 /Biochem. Biophys. Res. Commun. 256 (1) , 147—155 (1999) secretoglobin, family ID, member 2 / 32880—at / AW015055 / M-1006551 / P-1006542 / Biochem.Biophys.Res.Commun. 256 (1), 147—155 (1999)
==Transcription factor and related molecule (Transcriptional regulator pr otein) == == Transcription factor and related molecule (Transcriptional regulator protocol) ==
delta sleep inducing peptide, immunoreactor/36629_at/AI635895/NM_004089/N P— 004080 /Biochim. Biophys. Acta 1309 (3) , 200 - 204 (1996) delta sleep inducing peptide, immunoreactor / 36629_at / AI635895 / NM_004089 / NP-004080 / Biochim.Biophys.Acta 1309 (3), 200-204 (1996)
class I homeoprotein (H0XA9) /37809—at/U41813/應— 002142/NP— 002133/配列番 号： 1 3 (塩基配列） 配列番号： 1 4 (アミノ酸配列） beta-catenin-interacting protein ICAT/39171_at/W21787/NM_020248/NP_064633 /Genes Dev. 14 (14) , 1741-1749 (2000) class I homeoprotein (H0XA9) / 37809—at / U41813 / O—002142 / NP—002133 / SEQ ID NO: 13 (base sequence) SEQ ID NO: 14 (amino acid sequence) beta-catenin-interacting protein ICAT / 39171_at / W21787 / NM_020248 / NP_064633 / Genes Dev. 14 (14), 1741-1749 (2000)
promyelocytic leukemia zinc finger protein (PLZF) /39681_at/AF060568/M 一 006006/NP一 005997 /E B0 J. 12 (3)， 1161-1167 (1993) promyelocytic leukemia zinc finger protein (PLZF) / 39681_at / AF060568 / M-006006 / NP-005997 / E B0 J. 12 (3), 1161-1167 (1993)
GATA3 /40511— at/X58072/ M一 002051/NP一 002042 /EMB0 J. 10 (5) , 1187-1192 (1 991)  GATA3 / 40511—at / X58072 / M-002051 / NP-002042 / EMB0 J. 10 (5), 1187-1192 (1 991)
forkhead/winged helix-like transcription factor 7 (FKHL7) /41027_at/AF07forkhead / winged helix-like transcription factor 7 (FKHL7) / 41027_at / AF07
8096/NM一 001453/NP— 001444/Genomics 30 (3) , 464—469 (1995) 8096 / NM-001453 / NP— 001444 / Genomics 30 (3), 464—469 (1995)
Inhibitor of DNA binding 4 (ID4) /41536_at/AL022726/NM_001546/NP_001537/Ge nomics 1995 May 1 ;27 (1) :200-3  Inhibitor of DNA binding 4 (ID4) / 41536_at / AL022726 / NM_001546 / NP_001537 / Genomics 1995 May 1; 27 (1): 200-3
==Ion channel=  == Ion channel =
calcium channel, voltage-dependent, alpha 1H subun i t/ 37529_at/AF051946/NM _021098/NP_066921/Circ. Res. 83 (1)， 103-109 (1998) calcium channel, voltage-dependent, alpha 1H subunit / 37529_at / AF051946 / NM _021098 / NP_066921 / Circ.Res. 83 (1), 103-109 (1998)
sodium channel, nonvoltage-gated 1， beta/39682_at/X87159/ M_000336/NP_000sodium channel, nonvoltage-gated 1, beta / 39682_at / X87159 / M_000336 / NP_000
327/Genomics 28 (3) , 560-565 (1995) 327 / Genomics 28 (3), 560-565 (1995)
==Inhibin==  == Inhibin ==
Beta-mi croseminoprotein isoform a (PSP94) /32149_at/AA532495/N _002443/NP 一 002434/DNA 6 (1)， 23-29 (1987)  Beta-mi croseminoprotein isoform a (PSP94) / 32149_at / AA532495 / N_002443 / NP-002434 / DNA 6 (1), 23-29 (1987)
Beta-mi croseminoprotein isoform b (PSP57) /32149_at/U22178/NM_138634/NP_6 19540 /Oncogene 11 (6) , 1041-1047 (1995)  Beta-mi croseminoprotein isoform b (PSP57) / 32149_at / U22178 / NM_138634 / NP_6 19540 / Oncogene 11 (6), 1041-1047 (1995)
testicular inhibin beta-B-subunit /38545—at/M31682/NM— 002193/NP— 002184/B iochem. Biophys. Res. Commun. 135 (3) , 957-964 (1986) testicular inhibin beta-B-subunit / 38545—at / M31682 / NM— 002193 / NP— 002184 / B iochem. Biophys. Res.Commun. 135 (3), 957-964 (1986)
==0thers== == 0thers ==
==Membrane protein== == Membrane protein ==
LIGI (ortholog of mouse integral membrane glycoprotein LIG-l) /34800_at/AL 039458/AB050468/BAB40659/配列番号： 1 5 (塩基配列） 配列番号： 1 6 (アミ 1 6 LIGI (ortholog of mouse integral membrane glycoprotein LIG-l) / 34800_at / AL039458 / AB050468 / BAB40659 / SEQ ID NO: 15 (base sequence) SEQ ID NO: 16 (ami 1 6
ノ酸配列） Acid sequence)
WFSl (Wolfram syndrome 1) /35164_at/AF084481/NM_006005/ P_005996/Nat. Gen et. 20 (2)， 143-148 (1998)  WFSl (Wolfram syndrome 1) /35164_at/AF084481/NM_006005/P_005996/Nat.Gen et. 20 (2), 143-148 (1998)
TM4SF3 (transmembrane 4 superfamily member 3) /38469_at/M35252/NM_004616/N P_004607/Proc. Natl. Acad. Sci. U. S. A. 87 (17)， 6833-6837 (1990)  TM4SF3 (transmembrane 4 superfamily member 3) / 38469_at / M35252 / NM_004616 / N P_004607 / Proc. Natl. Acad. Sci. U.S.A. 87 (17), 6833-6837 (1990)
ITM2A (integral membrane protein 2A) /40775_at/AL021786/NM_004867/NP_00485 8/Mamm. Genome 10 (1) , 54-56 (1999) ITM2A (integral membrane protein 2A) / 40775_at / AL021786 / NM_004867 / NP_00485 8 / Mamm. Genome 10 (1), 54-56 (1999)
claudin 8/33610_at/AL049977/NM_012132/ P_036264/Nature 405 (6784) , 311-31 9 (2000) claudin 8 / 33610_at / AL049977 / NM_012132 / P_036264 / Nature 405 (6784), 311-31 9 (2000)
syndecan 4 (amphiglycan, ryudocan) /35844—at/D79206/N— 002999/NP一 002990/J. Cell Biol. 118 (4) , 961—969 (1992) syndecan 4 (amphiglycan, ryudocan) / 35844—at / D79206 / N— 002999 / NP-002990 / J. Cell Biol. 118 (4), 961-969 (1992)
progesterone receptor membrane component 2/38821_at/AJ002030/NM_006320/NP _006311/Biol. Chem. 379 (7) , 907-911 (1998) progesterone receptor membrane component 2 / 38821_at / AJ002030 / NM_006320 / NP _006311 / Biol.Chem. 379 (7), 907-911 (1998)
peanut-like 1 (Drosophila) /34412_s_at/U59632/NM_002688/NP_002679 /J. Biol. Chem. 269 (26)， 17424-17427 (1994) peanut-like 1 (Drosophila) / 34412_s_at / U59632 / NM_002688 / NP_002679 / J. Biol. Chem. 269 (26), 17424-17427 (1994)
angiotensin receptor 1， variantl/37983_at/S77410/NM_000685/NP_000676/Bioc hem. Biophys. Res. Commun. 183 (1) , 8 - 13 (1992) Angiotensin receptor 1, variantl / 37983_at / S77410 / NM_000685 / NP_000676 / Biochem. Biophys. Res.Commun. 183 (1), 8-13 (1992)
angiotensin receptor 1, variant2/37983_at/S77410/ M_009585/NP_033611/Bioc hem. Biophys. Res. Commun. 183 (1) , 8 - 13 (1992) angiotensin receptor 1, variant2 / 37983_at / S77410 / M_009585 / NP_033611 / Biochem. Biophys. Res.Commun. 183 (1), 8-13 (1992)
angiotensin receptor 1, var i ant 3/37983_at/S 77410/NM_004835/NP_004826/B i oc hem. Biophys. Res. Commun. 183 (1) , 8—13 (1992) Angiotensin receptor 1, var i ant 3 / 37983_at / S 77410 / NM_004835 / NP_004826 / B i oc hem. Biophys. Res.Commun. 183 (1), 8-13 (1992)
angiotensin receptor 1， variant4/37983_at/S77410/N _031850/NP_114038/Bioc hem. Biophys. Res. Commun. 183 (1) , 8—13 (1992) Angiotensin receptor 1, variant4 / 37983_at / S77410 / N _031850 / NP_114038 / Biochem. Biophys. Res. Commun. 183 (1), 8-13 (1992)
angiotensin receptor 1, variant5/37983_at/S77410/NM_032049/i P_114438/Bioc hem. Biophys. Res. Commun. 183 (1) , 8 - 13 (1992) angiotensin receptor 1, variant5 / 37983_at / S77410 / NM_032049 / i P_114438 / Biochem. Biophys.Res.Commun. 183 (1), 8-13 (1992)
EphB6/39930_at/D83492/ M_004445/NP_004436/Biochem. Biophys. Res. Commun. 235 (3)， 487-492 (1997) EphB6 / 39930_at / D83492 / M_004445 / NP_004436 / Biochem.Biophys.Res.Commun. 235 (3), 487-492 (1997)
proteolipid proteinl/41158_at/M54927/NM_000533/NP_000524/J. Neurosci. Res.proteolipid proteinl / 41158_at / M54927 / NM_000533 / NP_000524 / J. Neurosci. Res.
18 (3) , 395-401 (1987) 18 (3), 395-401 (1987)
==Secreted protein== == Secreted protein ==
betacellulin /33975_at/S55606/NM_001729/NP_001720/Biochem. Biophys. Res. Commun. 190 (3) , 1173-1179 (1993) betacellulin /33975_at/S55606/NM_001729/NP_001720/Biochem.Biophys.Res.Commun. 190 (3), 1173-1179 (1993)
apMl (adipose most abundant gene transcript D/40657一 r— at/Hi 5814/N— 00479 7/NP一 004788/Biochem. Biophys. Res. Commun. 221 (2)， 286—289 (1996) proline rich 4 (lacrimal) /36024_at/S79048/NM_007244/NP_009175 /Invest. Op hthalmol. Vis. Sci. 36 (10) , 2020-2031 (1995) apMl (adipose most abundant gene transcript D / 40657-r-at / Hi 5814 / N- 00479 7 / NP-004788 / Biochem.Biophys.Res.Commun.221 (2), 286-289 (1996) proline rich 4 ( lacrimal) / 36024_at / S79048 / NM_007244 / NP_009175 / Invest. Op hthalmol.Vis.Sci. 36 (10), 2020-2031 (1995)
=0thers== = 0thers ==
prolactin-inducible protein /41094_at/Y10179/NM_002652/NP_002643 /J. Biol.prolactin-inducible protein / 41094_at / Y10179 / NM_002652 / NP_002643 / J. Biol.
Chera. 262 (31) , 15236-15241 (1987) Chera. 262 (31), 15236-15241 (1987)
HZF9 /35026_f_at/X78932/X78932/CAA55532/DNA Cell Biol. 14 (2)， 125—136 (1 995) HZF9 / 35026_f_at / X78932 / X78932 / CAA55532 / DNA Cell Biol. 14 (2), 125-136 (1 995)
skin-specific protein (xp32) /31326_at/AF005081/AF005081/AAB83961/Genomic s 45 (2) , 250-258 (1997) skin-specific protein (xp32) / 31326_at / AF005081 / AF005081 / AAB83961 / Genomic s 45 (2), 250-258 (1997)
Crystallin, alpha B /32242_at/AL038340/N _001885/NP_001876/Genomics 7 (4) , 594-601 (1990)  Crystallin, alpha B / 32242_at / AL038340 / N _001885 / NP_001876 / Genomics 7 (4), 594-601 (1990)
retinol binding protein 4/32552_at/X00129/NM_006744/NP_006735/Nucleic Aci ds Res. 11 (22) , 7769—7776 (1983) retinol binding protein 4 / 32552_at / X00129 / NM_006744 / NP_006735 / Nucleic Acids Res. 11 (22), 7769-7777 (1983)
Hepatocellular carcinoma antigen gene 520/33007_at/AC002302/ M_022097/NP_ 071380/配列番号： 1 7 (塩基配列） 配列番号： 1 8 (アミノ酸配列）  Hepatocellular carcinoma antigen gene 520 / 33007_at / AC002302 / M_022097 / NP_ 071380 / SEQ ID NO: 17 (base sequence) SEQ ID NO: 18 (amino acid sequence)
DKFZP434G0310 (hypothetical protein) /33332—at/Z93241/-/-/配列番号： 1 9DKFZP434G0310 (hypothetical protein) / 33332—at / Z93241 /-/-/ SEQ ID NO: 19
(塩基配列） 配列番号： 2 0 (ァミノ酸配列） (Base sequence) SEQ ID NO: 20 (amino acid sequence)
Purkinje cell protein 4 (PCP4) /37576_at/U52969/ M_006198/NP_006189/Somat. Cell Mol. Genet. 22 (3) , 167 - 175 (1996) Purkinje cell protein 4 (PCP4) / 37576_at / U52969 / M_006198 / NP_006189 / Somat. Cell Mol. Genet. 22 (3), 167-175 (1996)
141H5/37630— t/AL049176/BC002909/AAH02909/配列番号： 2 1 (塩基配列） 配 列番号： 2 2 (アミノ酸配列）  141H5 / 37630—t / AL049176 / BC002909 / AAH02909 / SEQ ID NO: 21 (base sequence) SEQ ID NO: 22 (amino acid sequence)
cycl in Dl/38418_at/X59798/N _053056/NP_444284/Nature 350 (6318)， 512-515 (1991) cycl in Dl / 38418_at / X59798 / N _053056 / NP_444284 / Nature 350 (6318), 512-515 (1991)
loricrin/38851_at/M63394/NM_000427/NP_000418 /J. Biol. Chem. 266 (10) , 66 26-6636 (1991) loricrin / 38851_at / M63394 / NM_000427 / NP_000418 / J. Biol. Chem. 266 (10), 66 26-6636 (1991)
TRIM2 (tripartite motif-containing 2)/39382_at/AB011089/ M_015271/NP_0560 86/EMBO J. 20 (9) , 2140-2151 (2001)  TRIM2 (tripartite motif-containing 2) / 39382_at / AB011089 / M_015271 / NP_0560 86 / EMBO J. 20 (9), 2140-2151 (2001)
metallothionein IV (MTIV) /521_at/U07807/NM_032935/NP_l 16324 /Biochemistrymetallothionein IV (MTIV) / 521_at / U07807 / NM_032935 / NP_l 16324 / Biochemistry
33 (23)， 7250-7259 (1994) 33 (23), 7250-7259 (1994)
DKFZp586H2123 /40017_at/AL050214/AK027841/BAB55404/配列番号： 2 3 (塩基配 列） 配列番号： 2 4 (ァミノ酸配列） DKFZp586H2123 / 40017_at / AL050214 / AK027841 / BAB55404 / SEQ ID NO: 23 (base sequence) SEQ ID NO: 24 (amino acid sequence)
transmembrane 4 superfamily member 11 、plasmolipin)/41688—at/AI688299/I¾_ 015993/NP— 057077 /J Biol Chem 1994 Oct 7 ;269 (40) :24912-9 transmembrane 4 superfamily member 11, plasmolipin) / 41688—at / AI688299 / I¾_015993 / NP—057077 / J Biol Chem 1994 Oct 7; 269 (40): 24912-9
DKFZp434A202 /33690— at/AL080190/- /- /配列番号： 2 5 (塩基配列） DKFZp434A202 / 33690—at / AL080190 /-/-/ SEQ ID NO: 25 (base sequence)
KIAA0471/34445_at/AB007940/N _014857/ P_055672/DNA Res. 4 (5) , 345-349 (1 997) KIAA0471 / 34445_at / AB007940 / N _014857 / P_055672 / DNA Res. 4 (5), 345-349 (1 997)
KIAA0450 /35454_at/AB007919/NM_014638/NP_055453/DNA Res. 4 (5)， 345-349 (1997)  KIAA0450 / 35454_at / AB007919 / NM_014638 / NP_055453 / DNA Res. 4 (5), 345-349 (1997)
KIAA0624/35579_at/AB014524/NM_015065/NP_055880/J. Biol. Chem. 277 (11) , 9 212-9218 (2002)  KIAA0624 / 35579_at / AB014524 / NM_015065 / NP_055880 / J. Biol. Chem. 277 (11), 9 212-9218 (2002)
KIAA0633, partial cds /35669_at/AB014533/AB014533/BAA31608/DNA Res. 5 (3) :  KIAA0633, partial cds / 35669_at / AB014533 / AB014533 / BAA31608 / DNA Res. 5 (3):
169-176 (1998)  169-176 (1998)
KIAA0456, partial cds /36069_at/AB007925/AB007925/BAA32301/DNA Res. 4 (5) , 345—349 (1997) DKFZp564D206 /39577— at/AL050024/- /CAB43243/配列番号： 2 6 (塩基配列） 配列番号： 2 7 (アミノ酸配列） KIAA0456, partial cds / 36069_at / AB007925 / AB007925 / BAA32301 / DNA Res. 4 (5), 345-349 (1997) DKFZp564D206 / 39577—at / AL050024 /-/ CAB43243 / SEQ ID NO: 26 (base sequence) SEQ ID NO: 27 (amino acid sequence)
DKFZp586F1223 /39625__at/AL050204/-/-/配列番号： 2 8 (塩基配列）  DKFZp586F1223 / 39625__at / AL050204 /-/-/ SEQ ID NO: 28 (base sequence)
Clorf21/41679_at/AF035282/NM_030806/NP_110433/Genomics 73 (2)， 211-222 (2 001) Clorf21 / 41679_at / AF035282 / NM_030806 / NP_110433 / Genomics 73 (2), 211-222 (2 001)
DKFZp761F2014/41837—at/M149431/ L020215/ P— 064600/配列番号： 2 9 (塩基 配列） 配列番号： 3 0 (アミノ酸配列） 一データ 3  DKFZp761F2014 / 41837—at / M149431 / L020215 / P—064600 / SEQ ID NO: 29 (base sequence) SEQ ID NO: 30 (amino acid sequence) One data 3
(アトピー性皮膚炎患者の無疹部における発現レベルが、 健常者の発現レベル に比べて高い指標遺伝子群）  (Indicator genes whose expression level in the eruption area of patients with atopic dermatitis is higher than that in healthy subjects)
==Kinase and phosphatase:: == Kinase and phosphatase ::
P13- kinase associated p85 /1269— at/M61906/- / -/ Cell 65 (1) , 83-90 (1991)/ 配列番号： 3 1 (塩基配列） 配列番号： 3 2 (アミノ酸配列）  P13- kinase associated p85 / 1269— at / M61906 /-/-/ Cell 65 (1), 83-90 (1991) / SEQ ID NO: 31 (base sequence) SEQ ID NO: 32 (amino acid sequence)
phosphoenolpyruvate carboxykinase (PCKl) /33702— f— at/L05144/NM— 002591/ P— 002582/Hum. Mol. Genet. 2 (1)， 1-4 (1993) phosphoenolpyruvate carboxykinase (PCKl) / 33702—f—at / L05144 / NM—002591 / P—002582 / Hum. Mol. Genet. 2 (1), 1-4 (1993)
nucleotide pyrophosphatase/342_at/D12485/NM_006208/NP_006199/Arch. Bioche ra. Biophys. 295 (1) , 180 - 187 (1992) nucleotide pyrophosphatase / 342_at / D12485 / NM_006208 / NP_006199 / Arch.Bioche ra.Biophys. 295 (1), 180-187 (1992)
L-3-p osphoserine phosphatase /36736_f_at/Y10275/N¾L004577/ P_004568/FEBS L-3-p osphoserine phosphatase / 36736_f_at / Y10275 / N¾L004577 / P_004568 / FEBS
Lett. 408 (3) , 281-284 (1997) Lett. 408 (3), 281-284 (1997)
L—3-phosphoserine- phosphatase homologue/37208_at/AJ001612/ M_003832/NP_00 3823/Gene 210 (2) , 297 - 306 (1998) L-3-phosphoserine- phosphatase homologue / 37208_at / AJ001612 / M_003832 / NP_00 3823 / Gene 210 (2), 297-306 (1998)
KIAA0369 I doublecortin and CaM kinase— like l/38957_at/AB002367/NM_004734 /NP_004725/DNA Res. 4 (2)， 141—150 (1997)  KIAA0369 I doublecortin and CaM kinase— like l / 38957_at / AB002367 / NM_004734 / NP_004725 / DNA Res. 4 (2), 141—150 (1997)
tartrate-resistant acid phosphatase type 5 /677_s_at/J04430/NM_001611/NP_ 001602/Gene 130 (2) , 201-207 (1993) ==Protease, Protein degradation, Protease inhibitor== tartrate-resistant acid phosphatase type 5 / 677_s_at / J04430 / NM_001611 / NP_ 001602 / Gene 130 (2), 201-207 (1993) == Protease, Protein degradation, Protease inhibitor ==
pM5 protein /33414_at/X57398/ M_014287/NP_055102/Genomics 60 (3) , 295-308 (1999) pM5 protein / 33414_at / X57398 / M_014287 / NP_055102 / Genomics 60 (3), 295-308 (1999)
ADAM9 (a disintegrin and metalloproteinase domain 9) /34761_r_at/U41766/N ADAM9 (a disintegrin and metalloproteinase domain 9) / 34761_r_at / U41766 / N
M— 003816/NP— 003807/J. Cell Biol. 132 (4) , 717-726 (1996) M— 003816 / NP— 003807 / J. Cell Biol. 132 (4), 717-726 (1996)
Ubiquitin- conjugating enzyme E2E l/37358_at/AI039880/NM_003341/NP_003332/ 配列番号： 3 3 (塩基配列） 配列番号： 3 4 (アミノ酸配列）  Ubiquitin- conjugating enzyme E2E l / 37358_at / AI039880 / NM_003341 / NP_003332 / SEQ ID NO: 33 (base sequence) SEQ ID NO: 34 (amino acid sequence)
DKFZp586H2123 /40017— at/AL050214/AK027841/BAB55404/配列番号： 3 5 (塩基配 列） 配列番号： 3 6 (ァミノ酸配列）  DKFZp586H2123 / 40017—at / AL050214 / AK027841 / BAB55404 / SEQ ID NO: 35 (base sequence) SEQ ID NO: 36 (amino acid sequence)
SPUVE (protease, serine, 23) /40078— at/AF015287/NM_007173/NP_009104/配列番 号： 1 (塩基配列） 配列番号： 2 (アミノ酸配列）  SPUVE (protease, serine, 23) / 40078—at / AF015287 / NM_007173 / NP_009104 / SEQ ID NO: 1 (base sequence) SEQ ID NO: 2 (amino acid sequence)
squamous cell carcinoma antigen 2 (SCCA2) /1549_s_at/U19557/-/AAA97553/Pr oc Natl Acad Sci U S A. 1995 Apr 11 ;92 (8) : 3147 - 51. squamous cell carcinoma antigen 2 (SCCA2) / 1549_s_at / U19557 /-/ AAA97553 / Proc Natl Acad Sci U S A. 1995 Apr 11; 92 (8): 3147-51.
==Cell adhesion, Cell-cell interaction= == Cell adhesion, Cell-cell interaction =
connexin 43 (GJAl, Cx43) /2018一 at/M65188/應— 000165/ P— 000156/J. Cell Biol.connexin 43 (GJAl, Cx43) / 2018-at / M65188 / O—000165 / P—000156 / J. Cell Biol.
Ill (2) , 589-598 (1990) Ill (2), 589-598 (1990)
plakophilin /32380_at/Z34974/NM_000299/NP_000290/J. Cell. Sci. 107 (Pt 8) , 2259-2270 (1994) plakophilin /32380_at/Z34974/NM_000299/NP_000290/J.Cell.Sci. 107 (Pt 8), 2259-2270 (1994)
desmocollin type 4 /32417— at/D17427/NM— 001941/NP— 001932/J. Biol. Chem. 26 9 (42) , 26295-26302 (1994) desmocollin type 4 / 32417— at / D17427 / NM— 001941 / NP— 001932 / J. Biol. Chem. 269 (42), 26295-26302 (1994)
integrin alpha- 2 subunit /41481— at/X17033/NM— 002203/NP— 002194/J. Cell Bio 1. 109 (1) , 397-407 (1989) integrin alpha-2 subunit / 41481— at / X17033 / NM— 002203 / NP— 002194 / J. Cell Bio 1.109 (1), 397-407 (1989)
H-cadherin /483_g_at/U59289/ M_001257/NP_001248/Nat. Med. 2 (7) , 776-782 (1996)  H-cadherin / 483_g_at / U59289 / M_001257 / NP_001248 / Nat.Med. 2 (7), 776-782 (1996)
neural cell adhesion molecule (CALL) /34193_at/AF002246/NM_006614/NP_0066 05/Hum. Genet. 103 (3) , 355-364 (1998) ==Extracellu丄 ar matrix protein== neural cell adhesion molecule (CALL) / 34193_at / AF002246 / NM_006614 / NP_0066 05 / Hum.Genet. 103 (3), 355-364 (1998) == Extracellu 丄 ar matrix protein ==
cartilage intermediate layer protein (CILP) /34985_at/AF035408/NM_003613/ NP— 003604/J. Biol. Chem. 273 (36) , 23469-23475 (1998) cartilage intermediate layer protein (CILP) / 34985_at / AF035408 / NM_003613 / NP—003604 / J. Biol. Chem. 273 (36), 23469-23475 (1998)
lumican /38038_at/U21128/N _002345/NP_002336/Genomics 27 (3) , 481—488 (19 95) lumican / 38038_at / U21128 / N _002345 / NP_002336 / Genomics 27 (3), 481—488 (1995)
chondroitin sulphate proteoglycan versican, VI splice - variant/38111一 at/Xchondroitin sulphate proteoglycan versican, VI splice-variant / 38111-ichi at / X
15998/NM一 004385/NP一 004376/EMBO J. 8 (10) , 2975-2981 (1989) 15998 / NM-1004385 / NP-1004376 / EMBO J. 8 (10), 2975-2981 (1989)
germline oligomer ic matrix protein (COMP) /40161_at/L32137/N _000095/NP_0germline oligomer ic matrix protein (COMP) / 40161_at / L32137 / N _000095 / NP_0
00086/Genomics 24 (3) , 435-439 (1994) 00086 / Genomics 24 (3), 435-439 (1994)
==Enzyrae (without protease, kinase, phosphatase) ==  == Enzyrae (without protease, kinase, phosphatase) ==
aspartylglucosamini dase /34181— at/X55330/NM— 000027/NP— 000018/E BO J. 10 (1)， 51-58 (1991) aspartylglucosamini dase / 34181— at / X55330 / NM— 000027 / NP— 000018 / E BO J. 10 (1), 51-58 (1991)
lysyl hydroxylase isoform 2 (PL0D2) /34795_at/U84573/NM_000935/NP_000926/ J. Biol. Chem. 272 (11) , 6831-6834 (1997) lysyl hydroxylase isoform 2 (PL0D2) / 34795_at / U84573 / NM_000935 / NP_000926 / J. Biol. Chem. 272 (11), 6831-6834 (1997)
phospholipase A2， group IIA (platelets, synovial fluid) /37017_at/M22430/N M_000300/NP_000291/J. Biol. Chem. 264 (10)， 5335-5338 (1989) phospholipase A2, group IIA (platelets, synovial fluid) / 37017_at / M22430 / N M_000300 / NP_000291 / J. Biol. Chem. 264 (10), 5335-5338 (1989)
GDP-L-fucose pyrophosphorylase (GFPP) /38139一 at/AF017445/NM一 003838/NP— 003 829/J. Biol. Chem. 273 (46) , 30165-30174 (1998) GDP-L-fucose pyrophosphorylase (GFPP) / 38139-at / AF017445 / NM- 003838 / NP— 003 829 / J. Biol. Chem. 273 (46), 30165-30174 (1998)
glycogen debranching enzyme isoform 1 (AGL) , alternatively spliced isofo rm/38252_s_at/U84007/NM_000028/NP_000019/Genoraics 38 (2)， 155-165 (1996) Gu protein / DDX21： DEAD/H (Asp- Glu— Ala - Asp/His) box polypeptide 21/40490 _at/U41387/N _004728/ P_004719/Nucleic Acids Res. 24 (7) , 1220-1224 (199 6) glycogen debranching enzyme isoform 1 (AGL), alternatively spliced isofo rm / 38252_s_at / U84007 / NM_000028 / NP_000019 / Genoraics 38 (2), 155-165 (1996) Gu protein / DDX21: DEAD / H (Asp-Glu—Ala-Asp / His) box polypeptide 21/40490 _at / U41387 / N _004728 / P_004719 / Nucleic Acids Res. 24 (7), 1220-1224 (199 6)
lipoprotein lipase /41209_at/M15856/NM_000237/NP_000228/Science 235 (479 6)， 1638-1641 (1987) lipoprotein lipase / 41209_at / M15856 / NM_000237 / NP_000228 / Science 235 (479 6), 1638-1641 (1987)
SMA5/41642_at/X75940/X83301/CAA58280/Maram. Genome 5 (12)， 791-796 (1994) ==Globin== SMA5 / 41642_at / X75940 / X83301 / CAA58280 / Maram. Genome 5 (12), 791-796 (1994) == Globin ==
hemoglobin, alpha l/31525_s_at/J00153/NM_000558/NP_000549/Proc. Natl. Aca d. Sci. U. S. A. 71 (6)， 2300-2304 (1974) hemoglobin, alpha l / 31525_s_at / J00153 / NM_000558 / NP_000549 / Proc. Natl. Aca d. Sci. U.S.A. 71 (6), 2300-2304 (1974)
hemoglobin, alpha 2/31525_s_at/J00153/NM_000517/NP_000508/Proc. Natl. Aca d. Sci. U. S. A. 71 (6)， 2300-2304 (1974) hemoglobin, alpha 2 / 31525_s_at / J00153 / NM_000517 / NP_000508 / Proc. Natl. Aca d. Sci. U.S.A. 71 (6), 2300-2304 (1974)
sickle cell beta-globin /31687_f_at/M25079/ _000518/ P_000509/Prog. Nucl eic Acid Res. Mol. Biol. 19， 165-175 (1976) sickle cell beta-globin / 31687_f_at / M25079 / _000518 / P_000509 / Prog. Nucleic Acid Res. Mol. Biol. 19, 165-175 (1976)
beta-globin (HBB) /32052_at/L48215/N¾L000518/NP_000509/Proc. Natl. Acad. S ci. U. S. A. 89 (10) , 4324-4328 (1992) beta-globin (HBB) /32052_at/L48215/N¾L000518/NP_000509/Proc.Natl.Acad.Sci.U.S.A. 89 (10), 4324-4328 (1992)
A - gamma globin /38585_at/ 91036/NM_000559/NP_000550/Cell 21 (3) , 627-638 (1980)  A-gamma globin / 38585_at / 91036 / NM_000559 / NP_000550 / Cell 21 (3), 627-638 (1980)
G - gamma globin/38585_at/M91036/ l_000184/NP_000175/Cell 21 (3) , 627-638 (1980)  G-gamma globin / 38585_at / M91036 / l_000184 / NP_000175 / Cell 21 (3), 627-638 (1980)
==Channel, Transporter and related molecule==  == Channel, Transporter and related molecule ==
phospholipid transfer prot ein/4008 l_at/L26232/NM_006227/NP_006218/ J. Biol.phospholipid transfer prot ein / 4008 l_at / L26232 / NM_006227 / NP_006218 / J. Biol.
Chem. 269 (12) , 9388-9391 (1994) Chem. 269 (12), 9388-9391 (1994)
ATP- binding cassette, sub-family G (WHITE) , member 1/41362— at/X91249/ M—0 04915/ P— 004906/Am. J. Hum. Genet. 59 (1) , 66-75 (1996) ATP-binding cassette, sub-family G (WHITE), member 1 / 41362—at / X91249 / M-0 04915 / P—004906 / Am.J.Hum.Genet. 59 (1), 66-75 (1996)
type 2 inositol 1， 4, 5-trisphosphate receptor/756— at/D26350/ M—002223/NP—0 02214/Recept. Channels 2 (1) , 9-22 (1994) type 2 inositol 1, 4, 5-trisphosphate receptor / 756—at / D26350 / M—002223 / NP-0 02214 / Recept.Channels 2 (1), 9-22 (1994)
MVP (major vault protein) /38064_at/X79882/ M_017458/NP_059447/Nat. Med. 1 MVP (major vault protein) / 38064_at / X79882 / M_017458 / NP_059447 / Nat.Med. 1
(6)， 578-582 (1995) (6), 578-582 (1995)
C0G5 (component of oligomeric golgi complex 5) /34737_at/AF058718/N _00634 8/NP一 006339/J. Biol. Chem. 273 (45) , 29565 - 29576 (1998) C0G5 (component of oligomeric golgi complex 5) / 34737_at / AF058718 / N _00634 8 / NP-006339 / J. Biol. Chem. 273 (45), 29565-29576 (1998)
==¾100 family proteins (small calcium binding protein) == == ¾100 family proteins (small calcium binding protein) ==
S100 calcium-binding protein A7 (psoriasin 1) /34458_at/AA586894/NM_00296 3/NP一 002954/J. Invest. Dermatol. 97 (4) , 701-712 (1991) S100 calcium-binding protein A7 (psoriasin 1) / 34458_at / AA586894 / NM_00296 3 / NP 002954 / J. Invest. Dermatol. 97 (4), 701-712 (1991)
CaN19 /2027_at/M87068/N _005978/NP_005969/Genomics 25 (3)， 638-643 (1995) CaN19 / 2027_at / M87068 / N _005978 / NP_005969 / Genomics 25 (3), 638-643 (1995)
==Def ense/ immunity protein (Immunoglobulin and related molecule- ··. ) == immunoglobulin lambda light chain (constant region) /33273_f_at/X57809/-/_ == Defense / immunity protein (Immunoglobulin and related molecule- ...) == immunoglobulin lambda light chain (constant region) / 33273_f_at / X57809 /-/ _
/配列番号： 3 (塩基配列） 配列番号： 4 (アミノ酸配列） / SEQ ID NO: 3 (base sequence) SEQ ID NO: 4 (amino acid sequence)
immunoglobulin heavy constant gamma 3/37864— s—at/Y14737/-/-/配列番号： 5immunoglobulin heavy constant gamma 3 / 37864— s—at / Y14737 /-/-/ SEQ ID NO: 5
(塩基配列） 配列番号： 6 (アミノ酸配列） (Base sequence) SEQ ID NO: 6 (amino acid sequence)
immunoglobulin kappa constant/38194_s— at/M63438/- /- /配列番号： 7 (塩基配 列） 配列番号： 8 (ァミノ酸配列） immunoglobulin kappa constant / 38194_s—at / M63438 /-/-/ SEQ ID NO: 7 (base sequence) SEQ ID NO: 8 (amino acid sequence)
major histocompatibility complex, class II, DQ beta l/36108_at/M16276/NM_ 002123/NP— 002114/1匪 nogenetics 33 (5-6) , 404-408 (1991) major histocompatibility complex, class II, DQ beta l / 36108_at / M16276 / NM_ 002123 / NP— 002114/1 marauder nogenetics 33 (5-6), 404-408 (1991)
CIQB (complement component 1， q subcomponent, beta polypeptide) /38796_at/ X03084/NM一 000491/NP一 000482/Biochem. J. 231 (3) , 729-735 (1985) CIQB (complement component 1, q subcomponent, beta polypeptide) / 38796_at / X03084 / NM-1 000491 / NP-1 0000482 / Biochem. J. 231 (3), 729-735 (1985)
==G-protein and related molecule= == G-protein and related molecule =
Guanine Nucleotide- Binding Protein Ral, Ras - Oncogene Related/1876一 at/ -/ NM 一 005402/NP一 005393/J. Biol. Chera. 264 (28) , 16383-16389 (1989)  Guanine Nucleotide- Binding Protein Ral, Ras-Oncogene Related / 1876-1 at /-/ NM-1005402 / NP-1 005393 / J. Biol. Chera. 264 (28), 16383-16389 (1989)
KIAA0440 /40805_at/AB007900/ M_015556/NP_056371/Mol. Cell. Biol. 19 (1)， 733-744 (1999) KIAA0440 / 40805_at / AB007900 / M_015556 / NP_056371 / Mol. Cell. Biol. 19 (1), 733-744 (1999)
腿 5/600— at/M28215/NM—004162/NP— 004153/配列番号： 3 7 (塩基配列） 配列番 号： 3 8 (アミノ酸配列） Thigh 5 / 600—at / M28215 / NM—004162 / NP—004153 / SEQ ID NO: 37 (base sequence) SEQ ID NO: 38 (amino acid sequence)
KIAA0400ゾ development- and differentiation-enhancing factor 2/39410— at/A B007860/NM_003887/NP_003878/DNA Res. 4 (5) , 307-313 (1997)  KIAA0400zo development- and differentiation-enhancing factor 2 / 39410—at / A B007860 / NM_003887 / NP_003878 / DNA Res. 4 (5), 307-313 (1997)
==し hemokine= == then hemokine =
alternative activated macrophage spec ific CC chemokine 1/32128 at/Y13710/ 應— 002988/NP— 002979/J. Immunol. 160 (3) , 1411—1418 (1998) alternative activated macrophage spec ific CC chemokine 1/32128 at / Y13710 / O—002988 / NP— 002979 / J. Immunol. 160 (3), 1411—1418 (1998)
CC- chemokine MCP-4 /37454_at/AJ001634/ M_005408/NP_005399/J. Leukoc. Biol.
Figure imgf000170_0001
CC- chemokine MCP-4 / 37454_at / AJ001634 / M_005408 / NP_005399 / J. Leukoc. Biol.
Figure imgf000170_0001
61 (3) , 353-360 (1997)  61 (3), 353-360 (1997)
==Cytoskeletal structural protein== == Cytoskeletal structural protein ==
small proline- rich protein IB (cornif in) /37160_at/ 19888/NM_003125/NP_003small proline- rich protein IB (cornif in) / 37160_at / 19888 / NM_003125 / NP_003
116/Proc. Natl. Acad. Sci. U. S. A. 89 (22) , 11026 - 11030 (1992) 116 / Proc. Natl. Acad. Sci. U.S.A. 89 (22), 11026-11030 (1992)
myosin heavy chain 12 (MY05A) /40571_at/U90942/ M_000259/NP_000250/Genomi cs 19 (3)， 407-416 (1994) myosin heavy chain 12 (MY05A) / 40571_at / U90942 / M_000259 / NP_000250 / Genomi cs 19 (3), 407-416 (1994)
=rransc:riptiona丄： regulator protein=  = rransc: riptiona 丄: regulator protein =
M0P3 /36896_s_at/AF044288/NM_001178/NP_001169/J. Biol. Chem. 272 (13) , 8 581-8593 (1997)  M0P3 / 36896_s_at / AF044288 / NM_001178 / NP_001169 / J. Biol. Chem. 272 (13), 8 581-8593 (1997)
RB18A /32064— at/Y13467/NM— 004774/NP一 004765/Oncogene 15 (25) , 3013-3024 (1 997)  RB18A / 32064—at / Y13467 / NM—004774 / NP-004765 / Oncogene 15 (25), 3013-3024 (1 997)
TTF- I interacting peptide 12 / RNA pol I and transcript release factor /3 6369_at/AF000421/-/AAC63404/EMB0 J. 17 (10)， 2855-2864 (1998)  TTF- I interacting peptide 12 / RNA pol I and transcript release factor / 3 6369_at / AF000421 /-/ AAC63404 / EMB0 J. 17 (10), 2855-2864 (1998)
Mad4 homolog (Mad4) /38639_at/AF040963/NM_006454/NP_006445/EMBO J. 14 (2 2)， 5646-5659 (1995) Mad4 homolog (Mad4) / 38639_at / AF040963 / NM_006454 / NP_006445 / EMBO J. 14 (22), 5646-5659 (1995)
pituitary tumor-transforming protein 1 /40412_at/AA203476/Ml_004219/NP_00 4210/Mol. Endocrinol. 13 (1) , 156-166 (1999) pituitary tumor-transforming protein 1 / 40412_at / AA203476 / Ml_004219 / NP_00 4210 / Mol.Endocrinol. 13 (1), 156-166 (1999)
SMAD5 /1952—s一 at/AF010607/N— 005903/NP一 005894/J. Biol. Chem. 273 (4) , 18 72-1879 (1998)  SMAD5 / 1952-s-at / AF010607 / N- 005903 / NP-005894 / J. Biol. Chem. 273 (4), 18 72-1879 (1998)
==Cell cycle related molecule::  == Cell cycle related molecule ::
G0S2 /38326_at/M69199/NM_015714/NP_056529/DNA Cell Biol. 10 (8)， 581-591 (1991)  G0S2 / 38326_at / M69199 / NM_015714 / NP_056529 / DNA Cell Biol. 10 (8), 581-591 (1991)
cyclin B /1945_at/M25753/ _031966/NP_114172/Cell 58 (5) , 833-846 (1989) Retinoblastoma l/1937_at/-/M26460/AAA69565/Biochem. Biophys. Res. Commun.cyclin B / 1945_at / M25753 / _031966 / NP_114172 / Cell 58 (5), 833-846 (1989) Retinoblastoma l / 1937_at /-/ M26460 / AAA69565 / Biochem. Biophys. Res. Commun.
160 (3)， 1061-1066 (1989) 160 (3), 1061-1066 (1989)
==CD antigen, Ig superfamily protein== M130 antigen extracellular variant (CD163) /31438_s_at/Z22971/N _004244/N P— 004235/Eur. J. Immunol. 23 (9)， 2320-2325 (1993) == CD antigen, Ig superfamily protein == M130 antigen extracellular variant (CD163) / 31438_s_at / Z22971 / N _004244 / NP— 004235 / Eur. J. Immunol. 23 (9), 2320-2325 (1993)
Z39IG /37976_at/AL034397/NM_007268/ P_009199/Biochim. Biophys. Acta 1492 (2-3) , 522-525 (2000)  Z39IG / 37976_at / AL034397 / NM_007268 / P_009199 / Biochim.Biophys.Acta 1492 (2-3), 522-525 (2000)
==Adipocyte - related molecule= == Adipocyte-related molecule =
perilipin/37122_at/AB005293/NM_002666/NP_002657/Genomics 48 (2)， 254-257 (1998) perilipin / 37122_at / AB005293 / NM_002666 / NP_002657 / Genomics 48 (2), 254-257 (1998)
apMl (adipose most abundant gene transcript 1) /40658_r_at/D45371/NM_00479 7/NP一 004788/Biochem. Biophys. Res. Conraiun. 221 (2) , 286-289 (1996) apMl (adipose most abundant gene transcript 1) / 40658_r_at / D45371 / NM_00479 7 / NP-004788 / Biochem.Biophys.Res.Conraiun.221 (2), 286-289 (1996)
==0thers== == 0thers ==
DKFZp586J0323/32454— at/AL080215/- /- /配列番号： 3 9 (塩基配列）  DKFZp586J0323 / 32454—at / AL080215 /-/-/ SEQ ID NO: 39 (base sequence)
KIAA1001/33193_at/AW052084/N _014960/ P_055775/DNA Res. 6 (1) , 63-70 (199 9) KIAA1001 / 33193_at / AW052084 / N _014960 / P_055775 / DNA Res. 6 (1), 63-70 (199 9)
KIAA0766 /35209_at/AB018309/NM_014805/NP_055620/DNA Res. 5 (5) , 277-286 (1998)  KIAA0766 / 35209_at / AB018309 / NM_014805 / NP_055620 / DNA Res. 5 (5), 277-286 (1998)
KIAA0101/38116_at/D14657/NM_014736/NP_055551/DNA Res. 2 (1) , 37-43 (1995) DJ971N18. 2/KIAA1162/40478_at/AL021396/NM_021156/NP_066979/DNA Res. 6 (5)， 329-336 (1999)  KIAA0101 / 38116_at / D14657 / NM_014736 / NP_055551 / DNA Res. 2 (1), 37-43 (1995) DJ971N18.2 / KIAA1162 / 40478_at / AL021396 / NM_021156 / NP_066979 / DNA Res.6 (5), 329-336 ( (1999)
lung type- I cell membrane-associated protein (Tla— 2) /41870_at/AF030428/N _006474/NP_006465/Am. J. Respir. Cell Mol. Biol. 19 (1)， 143 - 149 (1998) metallothionein IV (MTIV) /521_at/U07807 / M_032935/NP_116324/Biochemistrylung type- I cell membrane-associated protein (Tla-2) / 41870_at / AF030428 / N _006474 / NP_006465 / Am. J. Respir. Cell Mol. Biol. 19 (1), 143-149 (1998) metallothionein IV (MTIV ) / 521_at / U07807 / M_032935 / NP_116324 / Biochemistry
33 (23) , 7250-7259 (1994) 33 (23), 7250-7259 (1994)
UTY (ubiquitously transcribed tetratricopeptide repeat gene, Y chromosom e) /34477_at/AF000994/NM_007125/ P_009056/Science 278 (5338) , 675-680 (199 7) UTY (ubiquitously transcribed tetratricopeptide repeat gene, Y chromosom e) / 34477_at / AF000994 / NM_007125 / P_009056 / Science 278 (5338), 675-680 (199 7)
Apg-l/40354_at/AB023421/NM_014278/NP_055093/Gene 237 (1) , 21-28 (1999) HUNKI I CAP/39093_s_at/Y12059/NM_014299/NP_055114/Mol. Cell. Biol. 20 (1 7) , 6537-6549 (2000) Apg-l / 40354_at / AB023421 / NM_014278 / NP_055093 / Gene 237 (1), 21-28 (1999) HUNKI I CAP / 39093_s_at / Y12059 / NM_014299 / NP_055114 / Mol.Cell.Biol. 20 (1 7), 6537-6549 (2000)
FHL2 (four and a half LIM domains 2) /38422_s_at/U29332/NM_001450/NP_00144 1/Gene 210 (2)， 345-350 (1998)  FHL2 (four and a half LIM domains 2) / 38422_s_at / U29332 / NM_001450 / NP_00144 1 / Gene 210 (2), 345-350 (1998)
RBP4 (retinol binding protein 4, plasma) /32552_at/X00129/NM_006744/NP_006 735/Nucleic Acids Res. 11 (22)， 7769-7776 (1983) (X00129)  RBP4 (retinol binding protein 4, plasma) / 32552_at / X00129 / NM_006744 / NP_006 735 / Nucleic Acids Res. 11 (22), 7769-7776 (1983) (X00129)
ALG-2 I programmed cell death 6/37569_at/AF035606/NM_013232/NP_037364/Sci ence 271 (5248) , 521-525 (1996) 一データ 4 ALG-2 I programmed cell death 6 / 37569_at / AF035606 / NM_013232 / NP_037364 / Science 271 (5248), 521-525 (1996) One data 4
(アトピー性皮膚炎患者の無疹部における発現レベルが、 健常者の発現レベル に比べて低い指標遺伝子群）  (Indicator genes whose expression level in the eruption area of atopic dermatitis patients is lower than that in healthy subjects)
~ Transcript i onal regulator p:rotein= ~ Transcript i onal regulator p: rotein =
junD /1612_s_at/X56681/NM_005354/NP_005345/0ncogene 6 (4)， 561-566 (1991) c-jun proto oncogene /1895一 at/J04111/NM— 002228/NP— 002219/Proc, Natl. Acad. Sci. U. S. A. 85 (23) , 9148 - 9152 (1988) junD / 1612_s_at / X56681 / NM_005354 / NP_005345 / 0ncogene 6 (4), 561-566 (1991) c-jun proto oncogene / 1895 at / J04111 / NM— 002228 / NP— 002219 / Proc, Natl. Acad. Sci. USA 85 (23), 9148-9152 (1988)
c-fos /1915_s_at/V01512/NM_005252/NP_005243/Proc. Natl. Acad. Sci. U. S. A. 80 (11) , 3183-3187 (1983) c-fos / 1915_s_at / V01512 / NM_005252 / NP_005243 / Proc. Natl. Acad. Sci. U.S.A. 80 (11), 3183-3187 (1983)
G0S3 I Fos-B/36669_at/L49169/NM_006732/NP_006723/DNA Cell Biol. 15 (12) , 1025-1038 (1996) G0S3 I Fos-B / 36669_at / L49169 / NM_006732 / NP_006723 / DNA Cell Biol. 15 (12), 1025-1038 (1996)
c-myc oncogene /37724_at/V00568/NM_002467/NP_002458/Nature 303 (5919)， 72 5-728 (1983) c-myc oncogene / 37724_at / V00568 / NM_002467 / NP_002458 / Nature 303 (5919), 725-728 (1983)
jun - B/2049— s— at/M29039 /NM_002229/NP_002220/Nucleic Acids Res. 18 (10) , 3 047-3048 (1990) jun-B / 2049—s—at / M29039 / NM_002229 / NP_002220 / Nucleic Acids Res. 18 (10), 3047-3048 (1990)
ATF3 (activating transcription factor 3) /287—at/L19871/匪— 001674/NP一 001 665/J. Biol. Chem. 269 (22) , 15819 - 15826 (1994) 1 7 2; —一一 1 ATF3 (activating transcription factor 3) / 287—at / L19871 / Marauder—001674 / NP-001 665 / J. Biol. Chem. 269 (22), 15819-15826 (1994) 1 7 2; - eleven 1
AREB6/33439_at/D15050/NM_030751/NP_H0378/J. Biochem. 114 (6)， 849-855 (1 993)  AREB6 / 33439_at / D15050 / NM_030751 / NP_H0378 / J. Biochem. 114 (6), 849-855 (1993)
ETRIOI /36097_at/M62831/NM_004907/NP_004898/J. Biol. Chem. 266 (19)， 1215 7-12161 (1991)  ETRIOI / 36097_at / M62831 / NM_004907 / NP_004898 / J. Biol. Chem. 266 (19), 1215 7-12161 (1991)
ZFP36 (zinc finger protein 36)/40448_at/M92843/NM_003407/NP_003398/DNA Ce 11 Biol. 12 (1) , 73-88 (1993)  ZFP36 (zinc finger protein 36) / 40448_at / M92843 / NM_003407 / NP_003398 / DNA Ce 11 Biol. 12 (1), 73-88 (1993)
ets-2/1519_at/J04102/ _005239/NP_005230/Proc. Natl. Acad. Sci. U. S. A. 85ets-2 / 1519_at / J04102 / _005239 / NP_005230 / Proc. Natl. Acad. Sci. U.S.A. 85
(21)， 7862-7866 (1988) (21), 7862-7866 (1988)
EZF/36214_at/U70663/NM_004235/ P_004226/J. Biol. Chem. 273 (2)， 1026-1031EZF / 36214_at / U70663 / NM_004235 / P_004226 / J. Biol. Chem. 273 (2), 1026-1031
(1998) (1998)
MITF (microphthalraia-associated transcription factor) /38228_g_at/AB006909 / M— 000248/ P一 000239/Hum. Mol. Genet. 3 (4) , 553-557 (1994)  MITF (microphthalraia-associated transcription factor) / 38228_g_at / AB006909 / M— 000248 / P-000239 / Hum.Mol. Genet. 3 (4), 553-557 (1994)
EGRl (early growth response l)/789_at/X52541/NM_001964/NP_001955/Nucleic Acids Res. 18 (14), 4283 (1990) EGRl (early growth response l) / 789_at / X52541 / NM_001964 / NP_001955 / Nucleic Acids Res. 18 (14), 4283 (1990)
EGR2 (early growth response 2) /37863— at/J04076/N— 000399/NP— 000390/Proc. Natl. Acad. Sci. U. S. A. 85 (19)， 7164 - 7168 (1988) ·  EGR2 (early growth response 2) / 37863— at / J04076 / N— 000399 / NP— 000390 / Proc. Natl. Acad. Sci. U.S.A. 85 (19), 7164-7168 (1988)
BTG2 /36634_at/U72649/NM_006763/NP_006754/Nat. Genet. 14 (4) , 482-486 (19 96) BTG2 / 36634_at / U72649 / NM_006763 / NP_006754 / Nat.Genet. 14 (4), 482-486 (1996)
MAD-3 /1461一 at/M69043/ M— 020529/NP一 065390/Cell 65 (7) , 1281-1289 (1991) Idl /36617_at/X77956/NM_002165/NP_002156/Bi och ira. Biophys. Acta 1219 (1), 160-162 (1994)  MAD-3 / 1461 at / M69043 / M-020529 / NP-1 065390 / Cell 65 (7), 1281-1289 (1991) Idl / 36617_at / X77956 / NM_002165 / NP_002156 / Bi och ira. Biophys. Acta 1219 (1 ), 160-162 (1994)
Id2/41215_s_at/D13891/ _002166/NP_002157/Proc. Natl. Acad. Sci. U. S. A. 8 9 (4) , 1512-1516 (1992)  Id2 / 41215_s_at / D13891 / _002166 / NP_002157 / Proc.Natl.Acad.Sci.U.S.A. 89 (4), 1512-1516 (1992)
Id3 /37043_at/AL021154/NM_002167/NP_002158/EMBO J. 11 (7) , 2563-2571 (199 2)  Id3 / 37043_at / AL021154 / NM_002167 / NP_002158 / EMBO J. 11 (7), 2563-2571 (199 2)
==Nuclear receptor:: TR3 (nuclear receptor subfamily 4, group A, member 1) /279_at/L13740/NM_0== Nuclear receptor :: TR3 (nuclear receptor subfamily 4, group A, member 1) / 279_at / L13740 / NM_0
02135/NP_002126/J. Steroid Biochem. 34 (1-6) , 391-395 (1989) 02135 / NP_002126 / J. Steroid Biochem. 34 (1-6), 391-395 (1989)
NOT (nuclear receptor subfamily 4, group A, member 2) /547_s_at/S77154/NM_ NOT (nuclear receptor subfamily 4, group A, member 2) / 547_s_at / S77154 / NM_
006186/NP— 006177/Mol. Endocrinol. 8 (11) , 1583-1591 (1994) 006186 / NP— 006177 / Mol. Endocrinol. 8 (11), 1583-1591 (1994)
==Enzyme==  == Enzyme ==
CL 100 I dual specificity phosphatase 1/1005— at/X68277/NM一 004417/ P— 00440 8/Nature 359 (6396) , 644-647 (1992)  CL 100 I dual specificity phosphatase 1 / 1005— at / X68277 / NM-004417 / P— 00440 8 / Nature 359 (6396), 644-647 (1992)
cyclooxygenase-2 (hCox~2) /1069_at/U04636/NM_000963/NP_000954/Proc. Natl. Acad. Sci. U. S. A. 89 (16) , 7384-7388 (1992) cyclooxygenase-2 (hCox ~ 2) /1069_at/U04636/NM_000963/NP_000954/Proc.Natl.Acad.Sci.U.S.A. 89 (16), 7384-7388 (1992)
cytochrome P450 4F2 (CYP4F2) /1350_at/U02388/NM_001082/NP_001073/FEBS Let t. 348 (1) , 70-74 (1994) cytochrome P450 4F2 (CYP4F2) / 1350_at / U02388 / NM_001082 / NP_001073 / FEBS Let t. 348 (1), 70-74 (1994)
prostaglandin D2 synthase /216_at/M98539/NM_000954/ P_000945/Proc. Natl. Acad. Sci. U. S. A. 88 (9)， 4020-4024 (1991) prostaglandin D2 synthase / 216_at / M98539 / NM_000954 / P_000945 / Proc. Natl. Acad. Sci. U.S.A. 88 (9), 4020-4024 (1991)
Fatty acid desaturase l/39372_at/W26480/ _013402/ P_037534/J. Biol. Chem. Fatty acid desaturase l / 39372_at / W26480 / _013402 / P_037534 / J. Biol. Chem.
274 (52) , 37335-37339 (1999) 274 (52), 37335-37339 (1999)
Fatty acid desaturase 2 /32190— at/AL050118/NM_004265/NP— 004256/Genoraics 6 6 (2) , 175-183 (2000) Fatty acid desaturase 2 / 32190—at / AL050118 / NM_004265 / NP—004256 / Genoraics 6 6 (2), 175-183 (2000)
cholesterol 25- hydroxylase /32363_at/AF059214/NM_003956/NP_003947/J. Biol. Chem. 273 (51) , 34316-34327 (1998) cholesterol 25-hydroxylase / 32363_at / AF059214 / NM_003956 / NP_003947 / J.Biol.Chem. 273 (51), 34316-34327 (1998)
11-beta-hydroxys teroi d dehydrogenase (HSDll) /35702_at/M76665/NM_005525/N P_005516/J. Biol. Chem. 266 (25) , 16653 - 16658 (1991)  11-beta-hydroxys teroi d dehydrogenase (HSDll) /35702_at/M76665/NM_005525/NP_005516/J.Biol.Chem. 266 (25), 16653-16658 (1991)
glutaraate pyruvate transaminase (GPT) /34430_at/U70732/NM_005309/ P_00530 0/Genomics 40 (2) , 247-252 (1997) glutaraate pyruvate transaminase (GPT) / 34430_at / U70732 / NM_005309 / P_00530 / Genomics 40 (2), 247-252 (1997)
glycine decarboxylase /35192一 at/D90239/丽—000170/NP一 000161/J. Biol. Chem.glycine decarboxylase / 35192-at / D90239 / 丽 —000170 / NP-00100161 / J. Biol. Chem.
266 (5) , 3323-3329 (1991) 266 (5), 3323-3329 (1991)
ornithine decarboxylase (ODC) /36203_at/X16277/NM_002539/NP_002530/Nuclei
Figure imgf000175_0001
ornithine decarboxylase (ODC) / 36203_at / X16277 / NM_002539 / NP_002530 / Nuclei
Figure imgf000175_0001
c Acids Res. 17 (21〉， 8855-8856 (1989) c Acids Res. 17 (21), 8855-8856 (1989)
GADD34/ Protein phosphatasel regulatory submit 15A/37028一 at/U83981/NM一 01 4330/NP_055145/J. Biol. Chem. 272 (21) , 13731—13737 (1997)  GADD34 / Protein phosphatasel regulatory submit 15A / 37028 at / U83981 / NM-1 01 4330 / NP_055145 / J. Biol. Chem. 272 (21), 13731-13737 (1997)
carboxypeptidase Z /37248_at/U83411/NM_003652/NP_003643/J. Biol. Chem. 27 2 (16)， 10543-10550 (1997) carboxypeptidase Z / 37248_at / U83411 / NM_003652 / NP_003643 / J. Biol. Chem. 27 2 (16), 10543-10550 (1997)
DKFZp434J214 /39411— at/AL080156/- /CAB45747/配列番号： 4 0 (塩基配列） 配 列番号： 4 1 (アミノ酸配列）  DKFZp434J214 / 39411—at / AL080156 /-/ CAB45747 / SEQ ID NO: 40 (base sequence) SEQ ID NO: 41 (amino acid sequence)
==Cyclin— dependent kinase inhibitor= == Cyclin— dependent kinase inhibitor =
Cdk - inhibitor p57KIP2 /1787—at/U22398/NM— 000076/NP一 000067/Genes Dev. 9 (6)， 650-662 (1995)  Cdk-inhibitor p57KIP2 / 1787—at / U22398 / NM— 000076 / NP-1 000067 / Genes Dev. 9 (6), 650-662 (1995)
WAFl I eye 1 in-dependent kinase inhibitor 1A (p21, Cipl) /2031_s_at/U03106/ NM一 000389/NP— 000380/Cell 75 (4) , 817—825 (1993)  WAFl I eye 1 in-dependent kinase inhibitor 1A (p21, Cipl) / 2031_s_at / U03106 / NM-1-000389 / NP—000380 / Cell 75 (4), 817—825 (1993)
==G - protein, Regulator of G-protein signaling:: == G-protein, Regulator of G-protein signaling ::
GEM (GTP binding protein overexpressed in skeletal muscle) /37279_at/U1055 0/ M一 005261/NP一 005252/Science 265 (5169)， 241-244 (1994)  GEM (GTP binding protein overexpressed in skeletal muscle) / 37279_at / U1055 0 / M-005261 / NP-005252 / Science 265 (5169), 241-244 (1994)
G0S8 I RGS2 (regulator of G-protein signalling 2) /37701_at/L13463/NM_0029 23/NP— 002914/DNA Cell Biol. 13 (2)， 125-147 (1994) G0S8 I RGS2 (regulator of G-protein signaling 2) / 37701_at / L13463 / NM_0029 23 / NP— 002914 / DNA Cell Biol. 13 (2), 125-147 (1994)
A28-RGS14p /41779_at/U70426/NM_002928/NP_002919/Proc. Natl. Acad. Sci. U. S. A. 94 (15) , 7868-7872 (1997)  A28-RGS14p /41779_at/U70426/NM_002928/NP_002919/Proc.Natl.Acad.Sci.U.S.A. 94 (15), 7868-7872 (1997)
BL34 I regulator of G-protein signalling l/36575_at/S59049/ M_002922/NP_0 02913/ J. Immunol. 150 (9) , 3895-3904 (1993)  BL34 I regulator of G-protein signaling l / 36575_at / S59049 / M_002922 / NP_0 02913 / J. Immunol. 150 (9), 3895-3904 (1993)
==G protein-coupled receptors:: == G protein-coupled receptors ::
beta— 2— adrenergic receptor /610_at/M15169/NM_000024/NP_000015/Proc. Natl.beta— 2— adrenergic receptor / 610_at / M15169 / NM_000024 / NP_000015 / Proc. Natl.
Acad. Sci. U. S. A. 84 (1) , 46-50 (1987) Acad. Sci. U.S.A. 84 (1), 46-50 (1987)
==CD antigen- major group rhinovirus receptor (HRV) / ICAM— 1 (CD54) /32640_at/M24283/NM_0 00201/NP_000192/Cell 52 (6) , 925-933 (1988) == CD antigen- major group rhinovirus receptor (HRV) / ICAM— 1 (CD54) / 32640_at / M24283 / NM_0 00201 / NP_000192 / Cell 52 (6), 925-933 (1988)
HB15 I CD83/37536_at/Z11697/NM_004233/NP_004224/Blood 81 (2) , 454-461 (19 93)  HB15 I CD83 / 37536_at / Z11697 / NM_004233 / NP_004224 / Blood 81 (2), 454-461 (1993)
CD69 /37645_at/Z22576/NM_001781/NP_001772/J. Exp. Med. 178 (2) , 537-547 (1993)  CD69 / 37645_at / Z22576 / NM_001781 / NP_001772 / J. Exp.Med. 178 (2), 537-547 (1993)
secreted epithelial tumor mucin antigen (MUCl) / CD227/1083— s— at/M35093/N M_002456/NP_002447/J. Biol. Chem. 265 (25)， 15294-15299 (1990) secreted epithelial tumor mucin antigen (MUCl) / CD227 / 1083—s—at / M35093 / N M_002456 / NP_002447 / J. Biol. Chem. 265 (25), 15294-15299 (1990)
==Chemokine= == Chemokine =
SLC/36503_at/AB002409/NM_002989/NP_002980/J. Biol. Chem. 272 (31), 19518- 19524 (1997)  SLC / 36503_at / AB002409 / NM_002989 / NP_002980 / J. Biol. Chem. 272 (31), 19518-19524 (1997)
GR0-beta/37187_at/M36820/ _002089/NP_002080/Proc. Natl. Acad. Sci. U. S. A. GR0-beta / 37187_at / M36820 / _002089 / NP_002080 / Proc. Natl. Acad. Sci. U.S.A.
87 (19)， 7732-7736 (1990) 87 (19), 7732-7736 (1990)
==Growth factor== == Growth factor ==
amphiregulin (AR) /34898_at/M30704/NM_001657/NP_001648/ ol. Cell. Biol. 1 0 (5) , 1969-1981 (1990) amphiregulin (AR) /34898_at/M30704/NM_001657/NP_001648/ol.Cell.Biol.10(5), 1969-1981 (1990)
heparin- binding EGF- like growth factor/38037— at/M60278/NM—001945/NP— 00193heparin-binding EGF- like growth factor / 38037—at / M60278 / NM—001945 / NP—00193
6/Science 251 (4996), 936—939 (1991) 6 / Science 251 (4996), 936--939 (1991)
==0thers=  == 0thers =
KIAA0508 /33591_at/AB007977/-/-/DNA Res. 4 (5) , 345-349 (1997)/配列番 号： 4 2 (塩基配列） 配列番号： 4 3 (アミノ酸配列）  KIAA0508 / 33591_at / AB007977 /-/-/ DNA Res. 4 (5), 345-349 (1997) / SEQ ID NO: 42 (base sequence) SEQ ID NO: 43 (amino acid sequence)
DKFZp434A202 /33690— at/AL080190/-/- /配列番号： 2 5 (塩基配列）  DKFZp434A202 / 33690—at / AL080190 /-/-/ SEQ ID NO: 25 (base sequence)
DKFZp564F212 /33954— at/AL049988/- /- /配列番号： 4 4 (塩基配列）  DKFZp564F212 / 33954—at / AL049988 /-/-/ SEQ ID NO: 44 (base sequence)
KIAA0924 /35878_at/AB023141/N _014897/NP_055712/DNA Res. 6 (1)， 63 - 70 (19 KIAA0924 / 35878_at / AB023141 / N _014897 / NP_055712 / DNA Res. 6 (1), 63-70 (19
99) 99)
画 2 (RNA, U2 small nuclear) /36398_at/W28729/K03022/-/ J. Mol. Biol. 179 (2)， 157—169 (1984) RIGUI I PERI (period homolog 1) /36829_at/AF022991/NM_002616/NP_002607/Ce 11 90 (6)， 1003-1011 (1997) Image 2 (RNA, U2 small nuclear) / 36398_at / W28729 / K03022 /-/ J. Mol. Biol. 179 (2), 157-169 (1984) RIGUI I PERI (period homolog 1) / 36829_at / AF022991 / NM_002616 / NP_002607 / Ce 11 90 (6), 1003-1011 (1997)
metallothionein 2A/39081_at/Al547258/N _005953/NP_005944/Biochera. Int. 28metallothionein 2A / 39081_at / Al547258 / N _005953 / NP_005944 / Biochera. Int. 28
(3) , 451-460 (1992) (3), 451-460 (1992)
IPL I TSSC3 (tumor suppressing sub transferable candidate 3) /31888_s_at/AF 001294/ M_003311/NP_003302/Hum. Mol. Genet. 6 (12) , 2021-2029 (1997) Wnt inhibitory factor-l/35178_at/W27944/ M_007191/NP_009122/Nature 398 (6 726) , 431-436 (1999) IPL I TSSC3 (tumor suppressing sub transferable candidate 3) / 31888_s_at / AF 001294 / M_003311 / NP_003302 / Hum.Mol.Genet. 6 (12), 2021-2029 (1997) Wnt inhibitory factor-l / 35178_at / W27944 / M_007191 / NP_009122 / Nature 398 (6 726), 431-436 (1999)
APR (ATL- derived PMA— responsive gene) /41048— at/D90070/NMJ)21127/NP一 066 950/J. Virol. 64 (10) , 4632-4639 (1990)  APR (ATL-derived PMA—responsive gene) / 41048— at / D90070 / NMJ) 21127 / NP-066 950 / J. Virol. 64 (10), 4632-4639 (1990)
clone 23568, 23621, 23795, 23873 and 23874 mRNA /39394_at/AF007149/-/-/Ge nome Res. 7 (4) , 353—358 (1997) /配列番号： 4 5 (塩基配列） clone 23568, 23621, 23795, 23873 and 23874 mRNA / 39394_at / AF007149 /-/-/ Genome Res. 7 (4), 353-358 (1997) / SEQ ID NO: 45 (base sequence)
radiation- inducible immediate-early gene (IEX-l) /1237—at/S81914/ M— 003897 / P— 003888/Cancer Res. 56 (7) , 1498-1502 (1996) radiation- inducible immediate-early gene (IEX-l) / 1237—at / S81914 / M— 003897 / P— 003888 / Cancer Res. 56 (7), 1498-1502 (1996)
FABP7 (fatty acid binding protein 7, brain) /35185_at/AJ002962/NM_001446/N FABP7 (fatty acid binding protein 7, brain) / 35185_at / AJ002962 / NM_001446 / N
P_001437/Biochim. Biophys. Acta 1354 (1) , 24-28 (1997) P_001437 / Biochim. Biophys. Acta 1354 (1), 24-28 (1997)
galanin /35879— at/M77140/— /AAA60178/Diabetes 41 (1) , 82-87 (1992) clone 23933/36234_at/U79273/-/-/Genome Res. 7 (4) , 353-358 (1997) /配列番 号： 4 6 (塩基配列） galanin / 35879— at / M77140 / — / AAA60178 / Diabetes 41 (1), 82-87 (1992) clone 23933 / 36234_at / U79273 /-/-// Genome Res. 7 (4), 353-358 (1997) / SEQ ID NO: 4 6 (base sequence)
glucose transporter-like protein- ΠΙ (GLUT3) /36979_at/ 20681/NM_006931/NP _008862/J. Biol. Chem. 263 (30) , 15245-15248 (1988) glucose transporter-like protein- ΠΙ (GLUT3) / 36979_at / 20681 / NM_006931 / NP _008862 / J. Biol. Chem. 263 (30), 15245-15248 (1988)
cytokeratin 15 /37582_at/X07696/NM_002275/NP_002266/J. Cell Biol. 106 (4)， 1249-1261 (1988) cytokeratin 15 / 37582_at / X07696 / NM_002275 / NP_002266 / J.Cell Biol. 106 (4), 1249-1261 (1988)
CYR61 /38772_at/Yl 1307/NM_001554/NP_001545/Oncogene 14 (14) , 1753—1757 (1 997)  CYR61 / 38772_at / Yl 1307 / NM_001554 / NP_001545 / Oncogene 14 (14), 1753—1757 (1 997)
IgG Fc binding protein/39014_at/D84239/NM_003890/NP_003881/J. Biol. Chem. 272 (24) , 15232-15241 (1997) IgG Fc binding protein / 39014_at / D84239 / NM_003890 / NP_003881 / J. Biol. Chem. 272 (24), 15232-15241 (1997)
GADD45B (growth arrest and DNA— damage-indue ible， beta) /39822_s_at/AF07807 7/NM_015675/ P_056490/Cell 95 (4)， 521-530 (1998)  GADD45B (growth arrest and DNA—damage-indue ible, beta) / 39822_s_at / AF07807 7 / NM_015675 / P_056490 / Cell 95 (4), 521-530 (1998)
STAT induced STAT inhibitor-3/ SOCS-3/40968_at/AB004904/NM_003955/ P_0039 46/Biochem. Biophys. Res. Commun. 237 (1) , 79-83 (1997)  STAT induced STAT inhibitor-3 / SOCS-3 / 40968_at / AB004904 / NM_003955 / P_0039 46 / Biochem.Biophys.Res.Commun. 237 (1), 79-83 (1997)
tumor necrosis factor alpha inducible protein A20/595一 at/M59465/NM— 006290 / P一 006281/J. Biol. Chem. 265 (25) , 14705-14708 (1990) また以上の解析の結果に基づいて、 アトピー性皮膚炎の指標とすることがで きるマウス由来の遺伝子として次に示す遺伝子を同定した。 これらの遺伝子は、 いずれも本発明における指標遺伝子として用いることができる。 以下に示す各 遺伝子のデータは、 いずれも、 左から順に次の情報を記載している。 各情報は スラッシュ （/) で区切って示している。 各遺伝子の機能は、 対応するヒト遺伝 子の記載に基づいて明らかにすることができる。 tumor necrosis factor alpha inducible protein A20 / 595 at / M59465 / NM— 006290 / P-1 006281 / J. Biol. Chem. 265 (25), 14705-14708 (1990) The following genes were identified as genes derived from mice that can be used as indicators of atopic dermatitis. Any of these genes can be used as an indicator gene in the present invention. Each of the data for each gene shown below contains the following information in order from the left. Each piece of information is separated by a slash (/). The function of each gene can be determined based on the description of the corresponding human gene.
「マゥス遺伝子名およびシンポル」  "Mice Gene Names and Symbols"
「プローブ」 （GeneChipにおけるプローブ ID)  "Probe" (Probe ID in GeneChip)
「プ口ープの塩基配列のデザィンのために用いられた塩基配列のデータベース (GenBank)ァクセッションナンパー」  "Database of base sequence used for designing base sequence of puppet (GenBank) accession number"
「各指標遺伝子の塩基配列のデータベース（GenBank)ァクセッションナンバー」 「当該遺伝子の塩基配列を示す配列番号」  "Base number database (GenBank) accession number of each indicator gene" "Sequence number indicating the base sequence of the gene"
「各指標遺伝子によってコードされるァミノ酸配列のデータベース（GenBank)ァ クセッションナンパ一」  “Database of amino acid sequences encoded by each indicator gene (GenBank) accession number”
「当該遺伝子によってコードされるアミノ酸配列を示す配列番号」  "SEQ ID NO: indicating the amino acid sequence encoded by the gene"
「ReferenC e」 （当該遺伝子を報告した論文） "R e f e ren C e " (a paper reporting the gene)
「対応するヒト遺伝子のデータベース（GenBank)ァクセッションナンパ一」 「対応するヒト遺伝子の遺伝子名」
Figure imgf000179_0001
"Corresponding human gene database (GenBank) accession number""Corresponding human gene name"
Figure imgf000179_0001
一データ 5 One data 5
(ダニァレルゲン感作マゥスの耳介皮膚における発現レベルがダニァレルゲン 非感作マゥスの耳介皮膚に比べて高い指標遺伝子群）  (Indicator genes whose expression level in ear skin of sensitized mice is higher than that of non-sensitized mice)
Cathepsin C /101019_at/U74683/NM_009982/48/NP_034112/49/McGuire, MJ. et a 1, Biochim. Biophys. Acta 1351, 267-273 (1997) /X87212/cathepsin C/配列番 号： 4 8 (塩基配列） 配列番号： 4 9 (アミノ酸配列）  Cathepsin C / 101019_at / U74683 / NM_009982 / 48 / NP_034112 / 49 / McGuire, MJ.eta1, Biochim.Biophys.Acta 1351, 267-273 (1997) / X87212 / cathepsin C / SEQ ID NO: 48 (bases) Sequence) SEQ ID NO: 49 (amino acid sequence)
Matrix nietalloproteinase 9 /99957_at/X72795/N _013599/50/NP_038627/51/Tan aka, H. et al, Biochem. Biophys. Res. Commun. 190， 732-740 (1993) /J05070/ type IV collagenase (MMP-9) /配列番号： 5 0 (塩基配列） 配列番号： 5 1 (アミノ酸配列）  Matrix nietalloproteinase 9 / 99957_at / X72795 / N _013599 / 50 / NP_038627 / 51 / Tan aka, H. et al, Biochem. Biophys. Res.Commun. 190, 732-740 (1993) / J05070 / type IV collagenase (MMP- 9) / SEQ ID NO: 50 (base sequence) SEQ ID NO: 51 (amino acid sequence)
Granzyme B /102877—at/M12302/NM— 013542/52/NP— 038570/53/Lobe, CG, et al, S cience 232, 858 - 861 (1986) /M17016/serine protease-like protein (granzyme B) /配列番号： 5 2 (塩基配列） 配列番号： 5 3 (アミノ酸配列）  Granzyme B / 102877—at / M12302 / NM— 013542/52 / NP— 038570/53 / Lobe, CG, et al, Science 232, 858-861 (1986) / M17016 / serine protease-like protein (granzyme B) / SEQ ID NO: 52 (base sequence) SEQ ID NO: 53 (amino acid sequence)
M. musculus 24p3 gene /160564_at/X81627/-/54/— /55/- /AI762213ん eutrophil ge latinase associated lipocalin (NGAL) /配列番号： 5 4 (塩基配列） 配列番 号： 5 5 (ァミノ酸配列） M. musculus 24p3 gene / 160564_at / X81627 /-/ 54 / — / 55 /-/ AI762213 eutrophil ge latinase associated lipocalin (NGAL) / SEQ ID NO: 54 (base sequence) SEQ ID NO: 55 (amino acid sequence) )
Interleukin 7 receptor /99030_at/M29697/NM_008372/56/NP_032398/57/Goodwin, RG. Et al, Cell 60, 941 - 951 (1990) /M29696/IL- 7R/配列番号： 5 6 (塩基配 列） 配列番号： 5 7 (ァミノ酸配列）  Interleukin 7 receptor / 99030_at / M29697 / NM_008372 / 56 / NP_032398 / 57 / Goodwin, RG.Etal, Cell 60, 941-951 (1990) / M29696 / IL-7R / SEQ ID NO: 56 (base sequence) Sequence No .: 5 7 (amino acid sequence)
Interleukin 6 /102218_at/X54542/NM_031168/58/NP_l 12445/59/Van Snick, J. et al, Eur. J. Immunol. 18, 193-197 (1988) /X04430/IL-6/配列番号： 5 8 (塩 基配列） 配列番号： 5 9 (アミノ酸配列）  Interleukin 6 / 102218_at / X54542 / NM_031168 / 58 / NP_l 12445/59 / Van Snick, J. et al, Eur. J. Immunol. 18, 193-197 (1988) / X04430 / IL-6 / SEQ ID NO: 58 (Base sequence) SEQ ID NO: 59 (amino acid sequence)
interleukin 4 receptor, alpha/102021— at/M27960 /蘭— 010557/60/NP— 034687/61/ Mosley, B. et al, Cell 59, 335-348 (1989) /X52425/IL- 4R/配列番号： 6 0 (塩 基配列） 配列番号： 6 1 (アミノ酸配列） interleukin 4 receptor, alpha / 102021— at / M27960 / orchid — 010557/60 / NP— 034687/61 / Mosley, B. et al, Cell 59, 335-348 (1989) / X52425 / IL-4R / SEQ ID NO: 60 (base sequence) SEQ ID NO: 61 (amino acid sequence)
Mus musculus cDNAん lone=2900006G01 /162850 at/AV150503/NM_010415/62/NP_0 34545/63/Abraham, JA. et al, Biochem. Biophys. Res. Commun. 190, 125 - 133 (1993) /M60278/hepar in-binding EGF - like growth factor /配列番号： 6 2 (塩 基配列） 配列番号： 6 3 (ァミノ酸配列） Mus musculus cDNA lone = 2900006G01 / 162850 at / AV150503 / NM_010415 / 62 / NP_0 34545/63 / Abraham, JA. Et al, Biochem. Biophys. Res. Commun. 190, 125-133 (1993) / M60278 / hepar in-binding EGF-like growth factor / SEQ ID NO: 62 (base sequence) SEQ ID NO: 63 (amino acid sequence)
Interleukin 3 receptor, beta chain 1 /11372 t/M34397/NM_007780/64/NP_03 1806/65/Gorman, DM, Proc. Natl. Acad. Sci. U. S. A. 87， 5459-5463 (1990) /HO 4668/GM-CSFR beta/配列番号： 6 4 (塩基配列） 配列番号： 6 5 (アミノ酸配 列）  Interleukin 3 receptor, beta chain 1/11372 t / M34397 / NM_007780 / 64 / NP_03 1806/65 / Gorman, DM, Proc. Natl. Acad. Sci. USA 87, 5459-5463 (1990) / HO 4668 / GM-CSFR beta / SEQ ID NO: 64 (base sequence) SEQ ID NO: 65 (amino acid sequence)
Small inducible cytokine A2 /102736_at/M19681 /NM— 011333/66/NP— 035463/67/ Kawahara, RS. and Deuel, TF. J. Biol. Chem. 264, 679-682 (1989) /M26683/MC P- 1/配列番号： 6 6 (塩基配列） 配列番号： 6 7 (アミノ酸配列）  Small inducible cytokine A2 / 102736_at / M19681 / NM— 011333/66 / NP— 035463/67 / Kawahara, RS. And Deuel, TF. J. Biol. Chem. 264, 679-682 (1989) / M26683 / MC P- 1 / SEQ ID NO: 66 (base sequence) SEQ ID NO: 67 (amino acid sequence)
Macrophage inflammatory protein 2 /101160— at/X53798 /NM_009140/68/NP_0331 66/69/Tekamp-01son, P. et al, J. Exp. Med. 172, 911-919 (1990) /M36820/GR0- 1^1&/配列番号： 6 8 (塩基配列） 配列番号： 6 9 (アミノ酸配列） Macrophage inflammatory protein 2 / 101160-at / X53798 / NM_009140 / 68 / NP_0331 66/69 / Tekamp-01son, P. et al, J. Exp.Med.172, 911-919 (1990) / M36820 / GR0-1 ^ 1 & / SEQ ID NO: 68 (base sequence) SEQ ID NO: 69 (amino acid sequence)
monocyte chemoattractant protein - 2 (MCP-2) precursoi"/92459— at/AB023418/NM _021443/70/NP_067418/71/Carninci, P. et al, Genome Res. 10, 1617—1630 (200 0) /Y16645/MCP - 2/配列番号： 7 0 (塩基配列） 配列番号： 7 1 (アミノ酸配 列） monocyte chemoattractant protein-2 (MCP-2) precursoi "/ 92459—at / AB023418 / NM _021443 / 70 / NP_067418 / 71 / Carninci, P. et al, Genome Res. 10, 1617-1630 (200 0) / Y16645 / MCP-2 / SEQ ID NO: 70 (base sequence) SEQ ID NO: 71 (amino acid sequence)
Chemokine (C-C) receptor 1 /99413— at/U29678 /NM— 009912/72/ P— 034042/73/Ga o, JL. and Murphy, PM. J. Biol. Chem. 270, 17494 - 17501 (1995) /D10925/CCR1/ 配列番号： 7 2 (塩基配列） 配列番号： 7 3 (アミノ酸配列）  Chemokine (CC) receptor 1 / 99413—at / U29678 / NM—009912 / 72 / P—034042 / 73 / Ga o, JL. And Murphy, PM.J. Biol. Chem. 270, 17494-17501 (1995) / D10925 / CCR1 / SEQ ID NO: 72 (base sequence) SEQ ID NO: 73 (amino acid sequence)
intracellular calcium-binding protein (MRP8) /103448_at/M83218 /NM一 013650 /74/NP— 038678/75/Lagasse, E. and Weissman, IL. Blood 79, 1907-1915 (1992) / AI126134/MRP- 8/配列番号： 7 4 (塩基配列） 配列番号： 7 5 (アミノ酸配列） intracellular calcium-binding protein (MRP14) /103887_at/M83219 /匪— 009114 /76/NP— 033140/77/Lagasse， E. and Weissman, IL. Blood 79, 1907 - 1915 (1992) / W72424/MRP- 14/配列番号： 7 6 (塩基配列） 配列番号： 7 7 (アミノ酸配列） 1 8ひ 」 intracellular calcium-binding protein (MRP8) / 103448_at / M83218 / NM-1 013650/74 / NP— 038678/75 / Lagasse, E. and Weissman, IL. Blood 79, 1907-1915 (1992) / AI126134 / MRP-8 / SEQ ID NO: 74 (base sequence) SEQ ID NO: 75 (amino acid sequence) intracellular calcium-binding protein (MRP14) / 103887_at / M83219 / marauder — 009114/76 / NP— 033140/77 / Lagasse, E. and Weissman, IL. Blood 79, 1907-1915 (1992) / W72424 / MRP-14 / SEQ ID NO: 76 (base sequence) SEQ ID NO: 77 (amino acid sequence) 1 8
complement receptor 3 beta subunit MAC— 1/102353— at/M31039 /NM_008404/78/N P— 032430/79/Wilson, RW. et al, Nucleic Acids Res. 17, 5397 (1989) /M15395/ leukocyte adhesion protein (LFA- 1/Mac - l/pl50, 95 family) beta /配歹幡号：complement receptor 3 beta subunit MAC— 1 / 102353—at / M31039 / NM_008404 / 78 / NP— 032430/79 / Wilson, RW.et al, Nucleic Acids Res. 17, 5397 (1989) / M15395 / leukocyte adhesion protein (LFA -1 / Mac-l / pl50, 95 family) beta / distribution system:
7 8 (塩基配列） 配列番号： 7 9 (アミノ酸配列） 7 8 (base sequence) SEQ ID NO: 7 9 (amino acid sequence)
upl4b05. xl /103506_f_at/AW228162/NI_013505/80/NP_038533/81/Buxton, RS. et al, Genomics 21, 510-516 (1994) /X56807/desmocollins type 2b /配列番号：upl4b05.xl / 103506_f_at / AW228162 / NI_013505 / 80 / NP_038533 / 81 / Buxton, RS. et al, Genomics 21, 510-516 (1994) / X56807 / desmocollins type 2b / SEQ ID NO:
8 0 (塩基配列） 配列番号： 8 1 (アミノ酸配列） 80 (base sequence) SEQ ID NO: 81 (amino acid sequence)
Tumor necrosis factor induced protein 6 /98474_r_at/U83903/ M_009398/82/N P_033424/83/Fulop, C. et al, Gene 202, 95-102 (1997) /M31165/TNFAIP6 (tumo r necrosis factor, alpha-induced protein 6) /配歹！]番号： 8 2 (塩基酉己列) 配列番号： 8 3 (アミノ酸配列）  Tumor necrosis factor induced protein 6 / 98474_r_at / U83903 / M_009398 / 82 / N P_033424 / 83 / Fulop, C. et al, Gene 202, 95-102 (1997) / M31165 / TNFAIP6 (tumo r necrosis factor, alpha-induced protein 6) / system! ] No .: 8 2 (base sequence) SEQ ID No .: 8 3 (amino acid sequence)
cell surface glycoprotein CD53 /94939_at/X97227/N¾L007651/84/NP_031677/85 /Wright, MD. et al, Int. Immunol. 5, 209-216 (1993) /M37033/CD53/酉己列番 号： 8 4 (塩基配列） 配列番号： 8 5 (アミノ酸配列） cell surface glycoprotein CD53 / 94939_at / X97227 / N¾L007651 / 84 / NP_031677 / 85 / Wright, MD. et al, Int. Immunol. 5, 209-216 (1993) / M37033 / CD53 / Toriki Column number: 8 4 ( SEQ ID NO: 85 (Amino acid sequence)
Mus musculus cDNA, 3 end /clone=4732410E23 /168294_f _at/AV236255/NM_0110 87/86/NP_035217/87/Kubagawa, H. et al, Proc. Natl. Acad. Sci. U. S. A. 94, 5261-5266 (1997) /AF025533/leucocyte i匪 noglobulin - like receptor— 3 (LIR— 3) /配列番号： 8 6 (塩基配列） 配列番号： 8 7 (アミノ酸配列）  Mus musculus cDNA, 3 end / clone = 4732410E23 / 168294_f _at / AV236255 / NM_0110 87/86 / NP_035217 / 87 / Kubagawa, H. et al, Proc. Natl. Acad. Sci. USA 94, 5261-5266 (1997) / AF025533 / leucocyte i marauder noglobulin-like receptor— 3 (LIR-3) / SEQ ID NO: 86 (base sequence) SEQ ID NO: 87 (amino acid sequence)
Tenascin C /101993— at/X56304/NM— 011607/88/NP— 035737/89/Weller, A. et al, J. Cell Biol. 112 (2) , 355-362 (1991) /X78565/Tenascin- C/配列番号： 8 8Tenascin C / 101993— at / X56304 / NM— 011607/88 / NP— 035737/89 / Weller, A. et al, J. Cell Biol. 112 (2), 355-362 (1991) / X78565 / Tenascin- C / SEQ ID NO: 8 8
(塩基配列） 配列番号： 8 9 (アミノ酸配列） (Base sequence) SEQ ID NO: 8 9 (amino acid sequence)
Mouse proteoglycan core protein /94085—at/M34603/NM— 011157/90/NP— 035287/9 1/Avrahara, S. et al, Proc. Natl. Acad. Sci. U. S. A. 86, 3763 - 3767 (1989) /X 17042/proteoglycan 1/配列番号： 9 0 (塩基配列） 配列番号： 9 1 (アミノ酸 配列） Mouse proteoglycan core protein / 94085—at / M34603 / NM— 011157/90 / NP— 035287/9 1 / Avrahara, S. et al, Proc. Natl. Acad. Sci. USA 86, 3763-3767 (1989) / X 17042 / proteoglycan 1 / SEQ ID NO: 90 (base sequence) SEQ ID NO: 91 (amino acid sequence)
Mouse beta Fc receptor type II (FCRII) /102337—s—at/M31312/丽— 010187/92/N
Figure imgf000182_0001
Mouse beta Fc receptor type II (FCRII) / 102337—s—at / M31312 / 丽 — 010187/92 / N
Figure imgf000182_0001
P_034317/93/Hibbs, ML. et al, Proc. Natl. Acad. Sci. U. S. A. 83, 6980 - 6984 (1986) /M31932/IgG low affinity Fc fragment receptor (CD32) /配列番号： 9 2 (塩基配列） 配列番号： 9 3 (アミノ酸配列）  Natl. Acad. Sci. USA 83, 6980-6984 (1986) / M31932 / IgG low affinity Fc fragment receptor (CD32) / SEQ ID NO: 92 (base sequence) P_034317 / 93 / Hibbs, ML. Et al, Proc. SEQ ID NO: 93 (amino acid sequence)
Hemopoietic cell kinase /93483_at/J03023/NM_010407/94/NP_034537/95/Klemsz, J. et al, Nucleic Acids Res. 15, 9600 (1987) /M16592/HCK/配列番号： 9 4 (塩基配列） 配列番号： 9 5 (ァミノ酸配列）  Hemopoietic cell kinase / 93483_at / J03023 / NM_010407 / 94 / NP_034537 / 95 / Klemsz, J. et al, Nucleic Acids Res. 15, 9600 (1987) / M16592 / HCK / SEQ ID NO: 94 (base sequence) SEQ ID NO: 9 5 (amino acid sequence)
Mouse mRNA for protein tyrosine phosphatase eps i lon/101932_at/D83484/N _0 11212/96/NP— 035342/97/Schepens, J. et al, Mol. Biol. Rep. 16， 241-248 (19 92) /X54134/protein tyrosine phosphatase, receptor type, E isoforml, 2/1B 列番号： 9 6 (塩基配列） 配列番号： 9 7 (アミノ酸配列） Mouse mRNA for protein tyrosine phosphatase eps ilon / 101932_at / D83484 / N _0 11212/96 / NP—035342 / 97 / Schepens, J. et al, Mol. Biol. Rep. 16, 241-248 (1992) / X54134 / protein tyrosine phosphatase, receptor type, E isoforml, 2 / 1B SEQ ID NO: 96 (base sequence) SEQ ID NO: 97 (amino acid sequence)
ma72f04. xl /129503_at/AI893884/- /98/- /99/- /U37100/aldose reductase- like p eptide /配列番号： 9 8 (塩基配列） 配列番号： 9 9 (アミノ酸配列） keratin 16 /103589_at/AF053235/NM_008470/100/NP_032496/101/Porter, RM. et al, J. Biol. Chem. 273, 32265-32272 (1998) /AF061812/keratin 16 (KRT16A) /配列番号： 1 0 0 (塩基配列） 配列番号： 1 0 1 (アミノ酸配列） ma72f04.xl / 129503_at / AI893884 /-/ 98 /-/ 99 /-/ U37100 / aldose reductase- like p eptide / SEQ ID NO: 98 (base sequence) SEQ ID NO: 99 (amino acid sequence) keratin 16 / 103589_at / AF053235 / NM_008470 / 100 / NP_032496 / 101 / Porter, RM. Et al, J. Biol. Chem. 273, 32265-32272 (1998) / AF061812 / keratin 16 (KRT16A) / SEQ ID NO: 100 (base sequence) SEQ ID NO: 101 (amino acid sequence)
Small proline— rich protein 2A /101024_i_at/AJ005559/NM_011468/102/NP_0355 98/103/Song, HJ. et al, Genomics 55 (1)， 28-42 (1999) /M21302/small prolin e-rich protein 2A/配列番号： 1 0 2 (塩基配列） 配列番号： 1 0 3 (ァミノ 酸配列） Small proline- rich protein 2A / 101024_i_at / AJ005559 / NM_011468 / 102 / NP_0355 98/103 / Song, HJ. Et al, Genomics 55 (1), 28-42 (1999) / M21302 / small prolin e-rich protein 2A / SEQ ID NO: 102 (base sequence) SEQ ID NO: 103 (amino acid sequence)
SPRRlb protein /100445_f_at/X91825/NM_009265/104/NP_033291/105/Kartasova, T. et al, J. Invest. Dermatol. 106, 294-304 (1996) /M19888/small proline - rich protein IB (com:if in) /配列番号： 1 0 4 (塩基配列） 配列番号： 1 0 5 (アミノ酸配列）  SPRRlb protein / 100445_f_at / X91825 / NM_009265 / 104 / NP_033291 / 105 / Kartasova, T. et al, J. Invest.Dermatol. 106, 294-304 (1996) / M19888 / small proline-rich protein IB (com: if in ) / SEQ ID NO: 104 (base sequence) SEQ ID NO: 105 (amino acid sequence)
Mus musculus cDNA /clone=2210020E15/164423_at/AV076807/NM_023065/106/NP_0 75552/107/Maric, M. et al, Science 294, 1361—1365 (2001) /J03909/gamma-IF N- inducible protein (IP- 30) /配列番号： 1 0 6 (塩基配列） 配列番号： 1 0 7 (アミノ酸配列） Mus musculus cDNA / clone = 2210020E15 / 164423_at / AV076807 / NM_023065 / 106 / NP_0 75552/107 / Maric, M. et al, Science 294, 1361-1365 (2001) / J03909 / gamma-IF N-inducible protein (IP- 30) / SEQ ID NO: 106 (base sequence) SEQ ID NO: 10 7 (amino acid sequence)
Signal transducer and activator of transcription 1/101465一 at/U06924/NM一 00 9283/108/NP_033309/109/Zhong, Z. et al, Science 264, 95 - 98 (1994)/M97936/ STAT1/配列番号： 108 (塩基配列） 配列番号： 109 (アミノ酸配列） Mus musculus cDNA, 3 endん lone=7330423G02 /161819_f _at/AV356071/ M_0106 86/110/NP_034816/lll/Adra, CN. et al, Genomics 35, 328-337 (1996)/U51240/ 丄 ysosomal - associated multitransmembrane protein (LAPTm5) /酉己列番号 : 110 Signal transducer and activator of transcription 1 / 101465-at / U06924 / NM-00 9283/108 / NP_033309 / 109 / Zhong, Z. et al, Science 264, 95-98 (1994) / M97936 / STAT1 / SEQ ID NO: 108 (Base sequence) SEQ ID NO: 109 (amino acid sequence) Mus musculus cDNA, 3 end lone = 7330423G02 / 161819_f _at / AV356071 / M_0106 86/110 / NP_034816 / lll / Adra, CN. Et al, Genomics 35, 328-337 (1996) / U51240 / 丄 ysosomal-associated multitransmembrane protein (LAPTm5)
(塩基配列） 配列番号： 1 1 1 (アミノ酸配列） (Base sequence) SEQ ID NO: 1 1 1 (amino acid sequence)
TYRO protein tyrosine kinase binding protein /100397_at/AF024637/ M_01166 2/112メ P— 035792/113/Lanier， LL. et al, Nature 391, 703 - 707 (1998)/W60864/ TYRO protein tyrosine kinase BP/配列番号： 112 (塩基配列） 配列番号： 1 13 (アミノ酸配列） TYRO protein tyrosine kinase binding protein / 100397_at / AF024637 / M_01166 2 / 112me P—035792 / 113 / Lanier, LL. Et al, Nature 391, 703-707 (1998) / W60864 / TYRO protein tyrosine kinase BP / SEQ ID NO: 112 (base sequence) SEQ ID NO: 1 13 (amino acid sequence)
—データ 6 —Data 6
(ダニァレルゲン感作マウスの耳介皮膚における発現レベルがダニァレルゲン 非感作マゥスの耳介皮膚に比べて低 、指標遺伝子群）  (Expression level in the auricle skin of mite-sensitized mice is lower than in the auricle skin of mite-sensitized mice, indicating a group of indicator genes)
MEP raRNA/102871_at/L77867/NM_007680/114/NP_031706/115/Gurniak, CB. and Be rg, LJ. Oncogene 13， 777-786 (1996)/D83492/EphB6/配列番号 : 1 14 (塩基配 列） 配列番号： 1 15 (アミノ酸配列）  MEP raRNA / 102871_at / L77867 / NM_007680 / 114 / NP_031706 / 115 / Gurniak, CB. And Be rg, LJ. Oncogene 13, 777-786 (1996) / D83492 / EphB6 / SEQ ID NO: 1 14 (base sequence) Sequence No .: 1 15 (amino acid sequence)
sciellin Putative 0rtholog/161132_at/AA727482^_022886/118/NP_075024/119 /Carninci, P. et al, Genome Res. 10, 1617 - 1630 (2000) /AF045941/sciellin (S CEL)/配列番号： 118 (塩基配列） 配列番号： 1 19 (アミノ酸配列） sciellin Putative 0rtholog / 161132_at / AA727482 ^ _022886 / 118 / NP_075024 / 119 / Carninci, P. et al, Genome Res. 10, 1617-1630 (2000) / AF045941 / sciellin (S CEL) / SEQ ID NO: 118 (base sequence ) SEQ ID NO: 1 19 (amino acid sequence)
Id4 dominant negative helix-loop-helix gene/96144— at/AJ001972/NM— 031166/1 20/NP_l 12443/121/Riechmann, V. et al, Nucleic Acids Res. 22, 749-755 (199 4)/AL022726/Inhibitor of DNA binding 4 (ID4)/配列番号 : 120 (塩基配列) 配列番号： 121 (アミノ酸配列） metallothionein 4 Putative Ortholog /102989—at/U07808/匪— 008631/124/NP— 03 2657/125/Quaife, CJ. et al， Biochemistry 33 (23)， 7250-7259 (1994)/U07807/ metallothionein IV (MTIV) /配列番号： 1 2 4 (塩基配列） 配列番号： 1.2 5 (アミノ酸配列） Id4 dominant negative helix-loop-helix gene / 96144— at / AJ001972 / NM— 031166/1 20 / NP_l 12443/121 / Riechmann, V. et al, Nucleic Acids Res. 22, 749-755 (199 4) / AL022726 / Inhibitor of DNA binding 4 (ID4) / SEQ ID NO: 120 (base sequence) SEQ ID NO: 121 (amino acid sequence) metallothionein 4 Putative Ortholog / 102989-at / U07808 / marauder-008631/124 / NP- 03 2657/125 / Quaife, CJ. et al, Biochemistry 33 (23), 7250-7259 (1994) / U07807 / metallothionein IV (MTIV ) / SEQ ID NO: 1 2 4 (base sequence) SEQ ID NO: 1.25 (amino acid sequence)
retinol binding protein (RBP) /96047_at/U63146/-/126/-/127/-/X00129/retino 1 inding protein 4/配列番号： 1 2 6 (塩基配列） 配列番号： 1 2 7 (アミ ノ酸配列） retinol binding protein (RBP) / 96047_at / U63146 /-/ 126 /-/ 127 /-/ X00129 / retino 1 inding protein 4 / SEQ ID NO: 1 2 6 (base sequence) SEQ ID NO: 1 2 7 (amino acid sequence )
RIKEN cDNA 0610006G05 gene /162986_at/AI841913/NM_025312/128/NP_079588/12 9/Carninci, P. et al， Genome Res. 10, 1617-1630 (2000) /AL050024/DKFZp564D 206/配列番号： 1 2 8 (塩基配列） 配列番号： 1 2 9 (アミノ酸配列）  RIKEN cDNA 0610006G05 gene / 162986_at / AI841913 / NM_025312 / 128 / NP_079588 / 12 9 / Carninci, P. et al, Genome Res. 10, 1617-1630 (2000) / AL050024 / DKFZp564D 206 / SEQ ID NO: 128 (bases) Sequence) SEQ ID NO: 1 2 9 (amino acid sequence)
〔実施例 3〕 アトピー性皮膚炎患者皮膚組織における、 ァフィメトリックス社 ジーンチップによるディファレンシャル発現解析 2  [Example 3] Differential expression analysis in skin tissue of atopic dermatitis patients using Affimetrics GeneChip 2
ァトピー性皮膚炎患者の皮膚組織で発現変動している新しい治療標的遺伝子 あるいは診断に有用な遺伝子を見出すことを目的として、 アトピー性皮膚炎患 者の無疹部、 急性病変部と健常人の正常皮膚で発現している遺伝子について、 ジーンチップを用いたディファレンシャルな発現比較解析を行った。  To find new therapeutic target genes whose expression is fluctuated in the skin tissue of atopic dermatitis patients or to find useful genes for diagnosis, there is no eruption, acute lesions in atopic dermatitis patients and normal For genes expressed in the skin, differential expression analysis using a gene chip was performed.
ァトピー性皮膚炎患者 12例、 健常人 7例から同意を得て、 患者からは無疹部 と急性病変部を、 健常人からは正常皮膚を、 各部位からそれぞれ 3個の皮膚検 体 （直径 3mm) を採取した。 急性病変部位は日本皮膚科学会の診断基準に基づき 判定した。 皮膚を採取したァドビー性皮膚炎患者の診療情報は上記表 1に示し た通りである。  With the consent of 12 patients with atopic dermatitis and 7 healthy subjects, three skin specimens (diameter: 3 mm). Acute lesion sites were determined based on the diagnostic criteria of the Japanese Dermatological Association. The clinical information of adobe dermatitis patients whose skin was collected is shown in Table 1 above.
ヒト皮膚からのジーンチップ解析用の RNA調製、 ジーンチップ用の cDNA合成、 DNAチップ解析は実施例 1に従って行つた。  RNA preparation for gene chip analysis from human skin, cDNA synthesis for gene chip, and DNA chip analysis were performed according to Example 1.
ァトピー性皮膚炎患者の無疹部と健常人の正常組織間で発現変動する遺伝子の 解析 2 Analysis of genes whose expression fluctuates between the eruption site of atopic dermatitis patients and normal tissues of healthy subjects 2
12例の各患者の無瘆部における遺伝子発現と健常人 7例の正常組織における 遺伝子発現の比較に DNAチップ解析ソフトである GeneSpring4. 2 (Silicon Gene tics社） を用いた。 GeneSpring User Manualに従い、 Af f ymetrix社解析ソフト Suite4. 0による Absolute Analysisの結果を GeneSpringに取り込んだ。 同一チ ップ上の全ての遺伝子について各遺伝子の Average Difference値をその median 値で割り、 チップ内補正値 （補正値 A) を得た。 さらに各遺伝子について、 使用 した全てのチップにおける補正値 Aをその median値で割ることによりネ甫正値 B を得た。 補正値 Bを用いてマン ·ホイットェ検定 （Mann- Whitney s U test) を 行い、 患者無疹部と健常皮膚間で発現量に有意差のある遺伝子を選択した。 選択した遺伝子群について、 更に、 患者無疹部と健常皮膚における各遺伝子 の発現量の平均値を比較して 2倍以上差のある遺伝子を選択した。 患者無疹部 に比較して健常皮膚で発現の高い遺伝子については健常人 7例のうち 4例以上 で！5 (present)となる遺伝子のみを選択し、 患者無疹部で発現の高い遺伝子に ついては患者 12例のうち 7例以上で Pとなる遺伝子のみを選択した。 結果を表 2 1〜表 2 4に示した。 Gene expression in the alveolar region of each of 12 patients and healthy subjects in 7 normal tissues GeneSpring4.2 (Silicon Genetics), a DNA chip analysis software, was used for gene expression comparison. According to the GeneSpring User Manual, the results of Absolute Analysis by Affymetrix analysis software Suite 4.0 were imported into GeneSpring. For each gene on the same chip, the average difference value of each gene was divided by its median value to obtain a correction value within the chip (correction value A). Furthermore, for each gene, the correction value A for all the chips used was divided by its median value to obtain a positive value B. Using the corrected value B, a Mann-Whitney's U test was performed, and genes having a significant difference in the expression level between the rash and the healthy skin were selected. From the selected gene group, the average value of the expression level of each gene in the non-rash area of the patient and the healthy skin was compared, and genes having a difference of at least 2-fold were selected. Genes that are more highly expressed in healthy skin than in the non-rash area of patients are more than 4 out of 7 healthy subjects! Only the gene that became 5 (present) was selected, and only the gene that became P in 7 or more of 12 patients was selected for the gene that was highly expressed in the rash of the patient. The results are shown in Tables 21 to 24.
Figure imgf000186_0001
Figure imgf000186_0001
1 8 6； 1 8 6;
表 2 2  Table 2 2
ァトピー性皮膚炎患者の無疹部と健常人の正常組織間の比較で、 ァトピー性 皮膚炎患者の無疹部で発現が減少していた遺伝子を示した。  A comparison between the non-rash area of atopic dermatitis patients and the normal tissue of healthy subjects showed genes whose expression was decreased in the non-rash areas of atopic dermatitis patients.
Figure imgf000187_0001
32798 at 2.56 0.98 0.042 AF043105 glutathione S-transferase M3 (brain)
Figure imgf000187_0001
32798 at 2.56 0.98 0.042 AF043105 glutathione S-transferase M3 (brain)
33202 f at 1.642 0.705 0.001 U43747 rnedreich ataxia  33202 f at 1.642 0.705 0.001 U43747 rnedreich ataxia
33220一 at 2.124 0.884 0.005 Z1 1773 zinc finger protein 187  33220 one at 2.124 0.884 0.005 Z1 1773 zinc finger protein 187
33240 at 2.419 0.916 0.023 AB029018 KIAA1095 protein  33240 at 2.419 0.916 0.023 AB029018 KIAA1095 protein
33439 at 2.361 0.804 9E-05 D 15050 AREB6  33439 at 2.361 0.804 9E-05 D 15050 AREB6
33773 at 1.804 0.864 0.01 U13948 MLLT10  33773 at 1.804 0.864 0.01 U13948 MLLT10
34093 at 1.944 0.915 0.01 AI829701 EST  34093 at 1.944 0.915 0.01 AI829701 EST
34388 at 3.516 0.836 0.002 Y11710 collagen, type XIV, alpha 1 (undulin)  34388 at 3.516 0.836 0.002 Y11710 collagen, type XIV, alpha 1 (undulin)
34778 at 2.412 1.029 0.03 AA418080 FLJ 12280  34778 at 2.412 1.029 0.03 AA418080 FLJ 12280
34820 at 2.351 0.829 0.013 M5739 pleiotrophin  34820 at 2.351 0.829 0.013 M5739 pleiotrophin
34898 at 2.389 0.652 0.017 M30704 amphiregulin (AR)  34898 at 2.389 0.652 0.017 M30704 amphiregulin (AR)
35007 at 1.548 0.751 0.001 AC004940 EST  35007 at 1.548 0.751 0.001 AC004940 EST
35399 at 1.796 0.896 0.03 AF102544 molybdenum cofactor synthesis 3  35399 at 1.796 0.896 0.03 AF102544 molybdenum cofactor synthesis 3
35735 at 2.176 0.826 9E-04 M55542 guanylate binding protein 1 , interferon-inducible, 67kDa  35735 at 2.176 0.826 9E-04 M55542 guanylate binding protein 1, interferon-inducible, 67kDa
35803 at 1.933 0.877 0.002 S82240 ras homolog gene family, member E  35803 at 1.933 0.877 0.002 S82240 ras homolog gene family, member E
00 00
35878 at 3.188 0.862 2E-05 AB023141 KIAA0924 35878 at 3.188 0.862 2E-05 AB023141 KIAA0924
36057 at 1.637 0.739 0.007 AB01 1084 armadillo repeat protein ALEX2  36057 at 1.637 0.739 0.007 AB01 1084 armadillo repeat protein ALEX2
36097 at 1.897 0.848 0.001 M62831 ETR101  36097 at 1.897 0.848 0.001 M62831 ETR101
36103 at 2.527 0.771 5E-04 D90144 MIP-1 -alpha  36103 at 2.527 0.771 5E-04 D90144 MIP-1 -alpha
36143 at 1.931 0.922 0.002 U13737 caspase 3, apoptosis-related cysteine protease  36143 at 1.931 0.922 0.002 U13737 caspase 3, apoptosis-related cysteine protease
36234 at 2.136 0.934 5E-04 U79273 clone 23933  36234 at 2.136 0.934 5E-04 U79273 clone 23933
36310 at 4.065 1.034 0.007 X86570 keratin, hair, acidic, 1  36310 at 4.065 1.034 0.007 X86570 keratin, hair, acidic, 1
36575 at 5.166 1.054 0.003 S59049 BL34 / regulator of G - protein signallin 1  36575 at 5.166 1.054 0.003 S59049 BL34 / regulator of G-protein signallin 1
36618 g at 1.85 0.92 0.002 X77956 Idl  36618 g at 1.85 0.92 0.002 X77956 Idl
36634 at 1.828 0.884 4E-05 U72649 BTG2  36634 at 1.828 0.884 4E-05 U72649 BTG2
36669 at 10.039 1.354 9E-04 L49169 G0S3 / Fos-B  36669 at 10.039 1.354 9E-04 L49169 G0S3 / Fos-B
36909 at 1.689 0.831 0.001 X62048 weel tyrosine kinase  36909 at 1.689 0.831 0.001 X62048 weel tyrosine kinase
36979 at 3.32 0.91 4E-05 M20681 glucose transporter-like protein-III (GLUT3)  36979 at 3.32 0.91 4E-05 M20681 glucose transporter-like protein-III (GLUT3)
37079 at 2.164 0.781 0.001 U82319 YDD19 protein  37079 at 2.164 0.781 0.001 U82319 YDD19 protein
37187 at 5.806 1.116 3E-04 M36820 GRO-beta  37187 at 5.806 1.116 3E-04 M36820 GRO-beta
37259 at 3.88 0.993 0.005 Z81326 serine (or cysteine) proteinase inhibitor, clade I (neuroserpin), member 1  37259 at 3.88 0.993 0.005 Z81326 serine (or cysteine) proteinase inhibitor, clade I (neuroserpin), member 1
37279 at 2.815 0.81 1 8E-06 U 10550 GtM ( GTP binding protein overexpressed in skeletal muscle )  37279 at 2.815 0.81 1 8E-06 U 10550 GtM (GTP binding protein overexpressed in skeletal muscle)
37536 at 1.931 0.795 0.002 Z11697 HB15 / CD83  37536 at 1.931 0.795 0.002 Z11697 HB15 / CD83
37623 at 13.291 1.264 1 E-04 X75918 NOT 37623 at 13.291 1.264 1 E-04 X75918 NOT
37643 at 2.005 0.882 0.003 X63717 CD95/ FAS 37643 at 2.005 0.882 0.003 X63717 CD95 / FAS
37645 at 2.842 0.623 2E-05 Z22576 CD69  37645 at 2.842 0.623 2E-05 Z22576 CD69
37724一 at 2.49 0.751 2E-05 V00568 c-myc oncogene  37724 ichi at 2.49 0.751 2E-05 V00568 c-myc oncogene
37764 at 9.496 0.657 6E-04 D87328 holocarboxyiase synthetase  37764 at 9.496 0.657 6E-04 D87328 holocarboxyiase synthetase
37860 at 2.209 0.99 0.002 AL049942 zinc finger protein 337  37860 at 2.209 0.99 0.002 AL049942 zinc finger protein 337
37927 at 1.66 0.701 0.023 X12654 chromosome condensation 1  37927 at 1.66 0.701 0.023 X12654 chromosome condensation 1
38037 at 21.15 1.459 0.002 60278 heparin-binding EGF-like growth factor  38037 at 21.15 1.459 0.002 60278 heparin-binding EGF-like growth factor
38058 at 1.764 0.795 2E-04 Z22865 dermatopontin  38058 at 1.764 0.795 2E-04 Z22865 dermatopontin
38125一 at 2.348 0.955 0.038 M 14083 SERPINE1  38 125 one at 2.348 0.955 0.038 M 14083 SERPINE1
38299 at 11.997 1.713 0.015 X04430 interleukin 6 (interferon, beta 2)  38299 at 11.997 1.713 0.015 X04430 interleukin 6 (interferon, beta 2)
38406 f at 2.1 13 1.004 0.018 AI207842 prostaglandin D2 synthase 21kDa (brain)  38406 f at 2.1 13 1.004 0.018 AI207842 prostaglandin D2 synthase 21kDa (brain)
38740 at 2.284 1.018 3E-04 X79067 zinc finger protein 36, C3H type-like 1  38740 at 2.284 1.018 3E-04 X79067 zinc finger protein 36, C3H type-like 1
38772 at 4.383 0.796 4E-05 Y11307 CYR61  38772 at 4.383 0.796 4E-05 Y11307 CYR61
39014 at 2.364 0.929 0.01 D84239 IgG Fc binding protein  39014 at 2.364 0.929 0.01 D84239 IgG Fc binding protein
391 at 1.967 0.904 0.03 X89416 protein phosphatase 5, catalytic subunit  391 at 1.967 0.904 0.03 X89416 protein phosphatase 5, catalytic subunit
39710— at 2.074 0.99 0.01 U30521 P31 1 protein  39710—at 2.074 0.99 0.01 U30521 P31 1 protein
39822 s at 2.381 0.9 0.001 AF078077 GADD45B ( growth arrest and DNA-damage - inducible, beta )
Figure imgf000189_0001
39822 s at 2.381 0.9 0.001 AF078077 GADD45B (growth arrest and DNA-damage-inducible, beta)
Figure imgf000189_0001
39829 at 1.897 0.536 9E-05 AB016811 ADP-ribosylation factor-like / ■' '  39829 at 1.897 0.536 9E-05 AB016811 ADP-ribosylation factor-like / ■ ''
39857 at 2.128 0.477 1 E-03 AF044309 syntaxin 11  39857 at 2.128 0.477 1 E-03 AF044309 syntaxin 11
40448 at 4.437 1.065 2E-04 92843 ZFP36 ( zinc finger protein 36 )  40448 at 4.437 1.065 2E-04 92843 ZFP36 (zinc finger protein 36)
40500 at 2.46 0.809 0.023 AF007138 NDRG family member 4  40500 at 2.46 0.809 0.023 AF007138 NDRG family member 4
41048 at 1.81 0.679 0.002 D90070 APR ( ATL - derived PMA-responsive gene )  41048 at 1.81 0.679 0.002 D90070 APR (ATL-derived PMA-responsive gene)
41 102 at 1.432 0.681 0.023 U66359 T54 protein  41 102 at 1.432 0.681 0.023 U66359 T54 protein
41779 at 1.735 0.755 2E-05 U70426 regulator of G— protein signallin 16  41779 at 1.735 0.755 2E-05 U70426 regulator of G— protein signallin 16
41852 at 1.859 0.909 9E-05 U22377 rearranged L-myc fusion sequence  41852 at 1.859 0.909 9E-05 U22377 rearranged L-myc fusion sequence
41864 at 1.983 0.985 0.023 AF052181 clone 24790  41864 at 1.983 0.985 0.023 AF052181 clone 24790
547 s at 11.475 1.026 1 E-04 S77154 nuclear receptor subfamily 4, group A, member 2  547 s at 11.475 1.026 1 E-04 S77154 nuclear receptor subfamily 4, group A, member 2
595 at 3.497 0.948 0.003 59465 tumor necrosis factor alpha inducible protein A20  595 at 3.497 0.948 0.003 59465 tumor necrosis factor alpha inducible protein A20
610 at 2.076 0.858 0.003 M15169 beta - 2 - adrenergic receptor  610 at 2.076 0.858 0.003 M15169 beta-2-adrenergic receptor
746 at 2.638 0.997 0.03 D50640 phosphodiesterase 3B  746 at 2.638 0.997 0.03 D50640 phosphodiesterase 3B
789一 at 1.941 0.847 9E-04 X52541 EGRl ( early growth response 1 )  789 at 1.941 0.847 9E-04 X52541 EGRl (early growth response 1)
875一 g— at 1.759 0.863 0.01 M26683 MCP1  875 g-at 1.759 0.863 0.01 M26683 MCP1
88 1 以上の解析の結果に基づいて、 アトピー性皮膚炎の指標とすることができる 遺伝子として次に示す遺伝子を同定した。 これらの遺伝子は、 いずれも本発明 における指標遺伝子として用いることができる。 以下に示す各遺伝子のデータ は、 いずれも、 左から順に次の情報を記載している。 各情報はスラッシュ （/) で区切って示している。 また指標遺伝子は、 各遺伝子の機能にしたがって、 分 類した。 分類された機能を =で示した。 88 1 Based on the results of the above analysis, the following genes were identified as genes that can be used as indicators of atopic dermatitis. Any of these genes can be used as an indicator gene in the present invention. Each of the data for each gene shown below lists the following information in order from the left. Each piece of information is separated by a slash (/). The indicator genes were classified according to the function of each gene. Classified functions are indicated by =.
「遺伝子名およぴシンボル」  "Gene name and symbol"
「プローブ」 (GeneChipにおけるプロープ ID)  "Probe" (Probe ID in GeneChip)
「プ口ーブの塩基配列のデザィンのために用いられた塩基配列のデータベース (GenBank)ァクセッションナンパー」  "Database of base sequence used for designing base sequence of probe (GenBank) accession number"
「各指標遺伝子の塩基配列のデータベース（GenBank)ァクセッションナンパー」 「各指標遺伝子によってコードされるァミノ酸配列のデータベース（GenBank)ァ クセッションナンパ一」  "Base sequence database of each indicator gene (GenBank) accession number" "Database of amino acid sequence encoded by each indicator gene (GenBank) accession number"
「Reference」 （当該遺伝子を報告した論文、 および塩基配列を配列表に記載し たものについてはその配列番号) "R e f e r ence" (papers reported the gene, and the sequence numbers are used for those described nucleotide sequence in the Sequence Listing)
一データ 7 ： One data 7:
(アトピー性皮膚炎患者の無疹部における発現レベルが、 健常者の発現レベル に比べて高い指標遺伝子群）  (Indicator genes whose expression level in the eruption area of patients with atopic dermatitis is higher than that in healthy subjects)
transforming growth factor, beta receptor III (betaglycan, 300kD) / 189 7— at I L07594 / M一 003243 / NP一 003234 I Biochem. Biophys. Res. Comraun. 189 (1) , 356-362 (1992) transforming growth factor, beta receptor III (betaglycan, 300kD) / 189 7- at I L07594 / M-003243 / NP-003234 I Biochem. Biophys. Res. Comraun. 189 (1), 356-362 (1992)
BTF3 protein homologue I 300_f_at I I M90355 / AAB04035 / Gene 117 (2) , 21.9—228 (1992)  BTF3 protein homologue I 300_f_at I I M90355 / AAB04035 / Gene 117 (2), 21.9—228 (1992)
hemoglobin, alpha 1 / 31525— s— at I J00153 /丽—000558 / NP一 000549 / Pro c Natl. Acad. Sci. U. S. A. 71 (6) , 2300-2304 (1974) hemoglobin, alpha 1/31525-s-at I J00153 / 丽 -000558 / NP-000549 / Pro c Natl. Acad. Sci. U.S.A. 71 (6), 2300-2304 (1974)
hemoglobin, beta / 31687— f— at I M25079 /丽— 000518 / NP— 000509 / Prog. Nucleic Acid Res. Mol. Biol. 19， 165 - 175 (1976) hemoglobin, beta / 31687— f—at I M25079 / 丽 —000518 / NP—000509 / Prog. Nucleic Acid Res. Mol. Biol. 19, 165-175 (1976)
alternative activated macrophage specific CC chemokine 1 / 32128一 at / Y 13710 I NM— 002988 / NP_002979 / J. Immunol. 160 (3) , 1411-1418 (1998) Prolactin— Induced Protein I 325— s一 at / / NM一 002652 / NP一 002643 / J. Bio 1. Chem. 262 (31) , 15236-15241 (1987) alternative activated macrophage specific CC chemokine 1/32128 at / Y 13710 I NM— 002988 / NP_002979 / J. Immunol. 160 (3), 1411-1418 (1998) Prolactin—Induced Protein I 325—s at // NM 002652 / NP 002643 / J. Bio 1.Chem. 262 (31), 15236-15241 (1987)
branched chain alpha-ketoacid dehydrogenase kinase / 32828一 at / AF02654 8 / L005881 / NP一 005872 / Am J Clin Nu r 1998 Jul ;68 (1) : 72 - 81 type I sigma receptor isoform 1 I 33879一 at / U79528 / NM— 005866 / NP— 00 5857 I J. Neurochem. 70 (2) , 443-451 (1998) branched chain alpha-ketoacid dehydrogenase kinase / 32828-1 at / AF02654 8 / L005881 / NP-005872 / Am J Clin Nu r 1998 Jul; 68 (1): 72-81 type I sigma receptor isoform 1 I 33879-1 at / U79528 / NM— 005866 / NP— 00 5857 I J. Neurochem. 70 (2), 443-451 (1998)
type I sigma receptor isoform 2 / 33879一 at / U79528 / ： NM一 147157 / NP一 67type I sigma receptor isoform 2/33879 at / U79528 /: NM 147 157 / NP 67
1513 I J, Neurochem. 70 (2) , 443-451 (1998) 1513 I J, Neurochem. 70 (2), 443-451 (1998)
type I sigma receptor isoform 3 / 33879一 at / U79528 / NM— 147158 / NP一 67type I sigma receptor isoform 3 / 33879-1 at / U79528 / NM— 147 158 / NP-1 67
1514 I J. Neurochem. 70 (2) , 443-451 (1998) 1514 I J. Neurochem. 70 (2), 443-451 (1998)
type I sigma receptor isoform 4 I 33879— at / U79528 / 蘭—147159 / NP— 67type I sigma receptor isoform 4 I 33879— at / U79528 / orchid—147159 / NP— 67
1515 I J. Neurochem. 70 (2) , 443-451 (1998) 1515 I J. Neurochem. 70 (2), 443-451 (1998)
type I sigma receptor isoform 5 I 33879一 at / U79528 / NM— 147160 / NP一 67type I sigma receptor isoform 5 I 33879 one at / U79528 / NM— 147 160 / NP one 67
1516 I J. Neurochem. 70 (2) , 443-451 (1998) 1516 I J. Neurochem. 70 (2), 443-451 (1998)
KIAA0664 protein / 34259一 at I AB014564 I NM— 015229 / NP— 056044 / DNA Re s. 5 (3) , 169-176 (1998)  KIAA0664 protein / 34259-I at I AB014564 I NM— 015229 / NP— 056044 / DNA Res. 5 (3), 169-176 (1998)
FK506— binding protein IB isoform a / 355_s_at / D38037 / NM— 004116 / NP FK506—binding protein IB isoform a / 355_s_at / D38037 / NM—004116 / NP
_004107 I Biochera. Biophys. Res. Co腿 un. 200 (2)， 836-843 (1994) _004107 I Biochera. Biophys. Res. Co Thigh un. 200 (2), 836-843 (1994)
FK506 - binding protein IB isoform b / 355— s— at / D38037 / NM— 054033 / NP 一 473374 I Biochem. Biophys. Res. Commun. 200 (2)， 836-843 (1994) lymphoid— restricted membrane protein (LRMP) / 35974一 at / U10485 / NM— 00 FK506-binding protein IB isoform b / 355—s—at / D38037 / NM—054033 / NP-473374 I Biochem. Biophys. Res.Commun. 200 (2), 836-843 (1994) lymphoid— restricted membrane protein (LRMP ) / 35974 one at / U10485 / NM— 00
6152 I NP— 006143 / J. Immunol. 153 (2) , 682-690 (1994) 6152 I NP— 006143 / J. Immunol. 153 (2), 682-690 (1994)
specific granule protein (28 kDa) (SGP28) / 36464— at / X94323 / 匪— 0060 61 I NP一 006052 / Eur. J. Biochem. 236 (3) , 827-836 (1996) ATPase, Ca++ transporting, ubiquitous / 36482— s一 at / Y15724 / NM一 005173 I NP一 005164 / Biochem. J. 318 (Pt 2) , 689-699 (1996) specific granule protein (28 kDa) (SGP28) / 36464— at / X94323 / marauder — 0060 61 I NP-006052 / Eur. J. Biochem. 236 (3), 827-836 (1996) ATPase, Ca ++ transporting, ubiquitous / 36482—s at at / Y15724 / NM-005173 I NP-005164 / Biochem. 318 (Pt 2), 689-699 (1996)
general transcription factor IIF, polypeptide 2, 30kDa / 36510一 at / X16 901 I NM一 004128 / NP一 004119 / Nature 341 (6241) , 10-414 (1989) carboxypeptidase M I 36708— at / J04970 / NM— 001874 / NP— 001865 / J. Bio 1. Chem. 264 (22) , 13165-13170 (1989) general transcription factor IIF, polypeptide 2, 30kDa / 36510 at / X16 901 I NM 004128 / NP 004119 / Nature 341 (6241), 10-414 (1989) carboxypeptidase MI 36708— at / J04970 / NM— 001874 / NP — 001865 / J. Bio 1. Chem. 264 (22), 13165-13170 (1989)
tyrosinase- related protein 1 / 36911— at / X51420 / NM— 000550 / NP— 00054 1 I Nucleic Acids Res. 18 (9) , 2807-2808 (1990) tyrosinase-related protein 1 / 36911—at / X51420 / NM—000550 / NP—00054 1 I Nucleic Acids Res. 18 (9), 2807-2808 (1990)
HCR (a- helix coiled - coil rod homologue) / 37425一 g一 at / AB029343 / NM一 01 9052 I NP一 061925 / - HCR (a- helix coiled-coil rod homologue) / 37425-g at
FLJ12525 I 38260— at / AL050306 / NM— 031206 / NP— 112483 /一 FLJ12525 I 38260—at / AL050306 / NM—031206 / NP—112483 / one
A— gamma globin / 38585— at / M91036 / NM_000559 / NP— 000550 / Cell 21 A—gamma globin / 38585—at / M91036 / NM_000559 / NP—000550 / Cell 21
(3) , 627-638 (1980) (3), 627-638 (1980)
complement component 1， q subcomponent, beta polypeptide / 38796— at / X 03084 I NM— 000491 / NP— 000482 / Biochem. J. 231 (3)， 729-735 (1985) SET binding factor 1 (SBFl) / 39835— at / U93181 / U93181 / AAC39675 / N at. Genet. 18 (4) , 331-337 (1998) complement component 1, q subcomponent, beta polypeptide / 38796— at / X 03084 I NM— 000491 / NP— 000482 / Biochem. J. 231 (3), 729-735 (1985) SET binding factor 1 (SBFl) / 39835— at / U93181 / U93181 / AAC39675 / N at.Genet. 18 (4), 331-337 (1998)
histidine ammonia-lyase / 40735— at / D16626 / NM— 002108 / NP— 002099 / B iochim. Biophys. Acta 1216 (2) , 293-295 (1993) histidine ammonia-lyase / 40735— at / D16626 / NM— 002108 / NP— 002099 / Biochim. Biophys. Acta 1216 (2), 293-295 (1993)
KIAA0440 I 40805一 at / AB007900 / NM— 015556 / NP一 056371 / MoL Cell. Bio 1. 19 (1) , 733-744 (1999)  KIAA0440 I 40805 at / AB007900 / NM— 015556 / NP 056371 / MoL Cell. Bio 1.19 (1), 733-744 (1999)
ESTs, Moderately similar to 2004399A chromosomal protein / 40884_g_at I W28230 I W28230 / - / - gap junction protein, beta 3， 31kD (connexin 31) / 41076— at / AF099730 I 丽—024009 I NP— 076872 / Biochem. Biophys. Res. Commun. 248 (3) , 910—9
Figure imgf000193_0001
ESTs, Moderately similar to 2004399A chromosomal protein / 40884_g_at I W28230 I W28230 /-/-gap junction protein, beta 3, 31kD (connexin 31) / 41076— at / AF099730 I 丽 —024009 I NP— 076872 / Biochem. Biophys. Res Commun. 248 (3), 910-9
Figure imgf000193_0001
15 (1998)  15 (1998)
androgen - regulated short-chain denydrogenase reductase 1 / 41172_at / A A126515 / NM— 016026 / NP— 057110 I Cancer Res. 61 (4) , 1611-1618 (2001) nuclear receptor subfamily 1, group H， member 2 / 518一 at / U07132 / NM— 007121 / NP— 009052 / Gene 147 (2)， 273-276 (1994) androgen-regulated short-chain denydrogenase reductase 1 / 41172_at / A A126515 / NM-016026 / NP-057110 I Cancer Res. 61 (4), 1611-1618 (2001) nuclear receptor subfamily 1, group H, member 2/518 at / U07132 / NM—007121 / NP—009052 / Gene 147 (2), 273-276 (1994)
matrilysin (M P7) / 668一 s一 at / L22524 / NM一 002423 / NP一 002414 / Biochem.matrilysin (M P7) / 668-1 s-1 at / L22524 / NM-1002423 / NP-1002414 / Biochem.
J. 253 (1)， 187-192 (1988) J. 253 (1), 187-192 (1988)
runt-related transcription factor 1 I 943— at / D43968 / NM— 001754 / P_ 001745 I Nucleic Acids Res. 23 (14) , 2762-2769 (1995) runt-related transcription factor 1 I 943— at / D43968 / NM— 001754 / P_ 001745 I Nucleic Acids Res. 23 (14), 2762-2769 (1995)
一データ 8 ： One data 8:
(アトピー性皮膚炎患者の無疹部における発現レベルが、 健常者の発現レベル に比べて低い指標遺伝子群）  (Indicator genes whose expression level in the eruption area of atopic dermatitis patients is lower than that in healthy subjects)
CL 100 dual specificity phosphatase 1 / 1005一 at / X68277 / NM_004417 I NP— 004408 I Nature 359 (6396) , 644-647 (1992)  CL 100 dual specificity phosphatase 1/1005 at / X68277 / NM_004417 I NP— 004408 I Nature 359 (6396), 644-647 (1992)
cyclooxygenase-2 (hCox— 2) I 1069— at / U04636 / NM一 000963 / NP— 000954 /cyclooxygenase-2 (hCox— 2) I 1069—at / U04636 / NM-000963 / NP—000954 /
Proc. Natl. Acad. Sci. U. S. A. 89 (16)， 7384—7388 (1992) Proc. Natl. Acad. Sci. U. S. A. 89 (16), 7384-7388 (1992)
T cell receptor delta locus I 1110— at / 21624 / M21624 / AAA61125 I Pr oc. Natl. Acad. Sci. U. S. A. 85 (15) , 5634-5638 (1988)  T cell receptor delta locus I 1110— at / 21624 / M21624 / AAA61125 I Pr oc. Natl. Acad. Sci. U.S.A. 85 (15), 5634-5638 (1988)
chorionic gonadotropin beta subunit / 1122— f一 at / K03183 / NM— 033142 /chorionic gonadotropin beta subunit / 1122— f-ichi at / K03183 / NM— 033142 /
NP— 149133 I J. Biol. Chem. 258 (19) , 11492—11499 (1983) NP—149133 I J. Biol. Chem. 258 (19), 11492—11499 (1983)
dual specificity phosphatase 2 / 1292— at / L11329 / NM— 004418 I NP— 0044dual specificity phosphatase 2 / 1292—at / L11329 / NM—004418 I NP—0044
09 I Science 259 (5102) , 1763—1766 (1993) 09 I Science 259 (5102), 1763-1766 (1993)
c-jun proto oncogene / 1895— at / J04111 / NM— 002228 / NP— 002219 / Proc. Natl. Acad. Sci. U. S. A. 85 (23) , 9148-9152 (1988) c-jun proto oncogene / 1895— at / J04111 / NM— 002228 / NP— 002219 / Proc. Natl. Acad. Sci. U.S.A. 85 (23), 9148-9152 (1988)
c-fos I 1915—s— at / V01512 / 丽ー 005252 / NP一 005243 / Proc. Natl. Acad. Sci. U. S. A. 80 (11) , 3183-3187 (1983) WAFl cycl in-dependent kinase inhibitor 1A (p21, Cipl) / 2031— s— at I U03 106 I NM— 000389 / NP— 000380 I Cell 75 (4) , 817-825 (1993) c-fos I 1915—s—at / V01512 / P-005252 / NP-005243 / Proc. Natl. Acad. Sci. USA 80 (11), 3183-3187 (1983) WAFl cycl in-dependent kinase inhibitor 1A (p21, Cipl) / 2031— s— at I U03 106 I NM— 000389 / NP— 000380 I Cell 75 (4), 817-825 (1993)
weel tyrosine kinase / 2033— s— at I U10564 / NM_003390 / MP— 003381 I Nat ure 353 (6339) , 80-83 (1991) weel tyrosine kinase / 2033— s— at I U10564 / NM_003390 / MP— 003381 I Nature 353 (6339), 80-83 (1991)
jun-B I 2049一 s— at / M29039 I NM一 002229 / NP— 002220 / Nucleic Acids Res.jun-B I 2049 s-at / M29039 I NM-002229 / NP— 002220 / Nucleic Acids Res.
18 (10)， 3047-3048 (1990) 18 (10), 3047-3048 (1990)
prostaglandin D2 synthase / 216_at / M98539 / NM— 000954 / NP— 000945 I P roc. Natl. Acad. Sci. U. S. A. 88 (9) , 4020-4024 (1991) prostaglandin D2 synthase / 216_at / M98539 / NM— 000954 / NP— 000945 I Proc. Natl. Acad. Sci. U.S.A. 88 (9), 4020-4024 (1991)
pleiotrophin / 234— s— at / M57399 / _002825 / NP— 002816 / Science 250 (4988) , 1690-1694 (1990) pleiotrophin / 234—s—at / M57399 / _002825 / NP—002816 / Science 250 (4988), 1690-1694 (1990)
TR3 (nuclear receptor subfamily 4, group A， member 1) / 279一 at / LI 3740 I NM一 002135 / NP— 002126 / J. Steroid Biochem. 34 (1—6)， 391-395 (1989) ATF3 (activating transcription factor 3) / 287— at / L19871 / NM— 001674 / NP— 001665 I J. Biol. Chem. 269 (22) , 15819-15826 (1994)  TR3 (nuclear receptor subfamily 4, group A, member 1) / 279-1 at / LI 3740 I NM-1 002135 / NP— 002126 / J. Steroid Biochem. 34 (1-6), 391-395 (1989) ATF3 (activating transcription factor 3) / 287-at / L19871 / NM-001674 / NP-001665 I J. Biol. Chem. 269 (22), 15819-15826 (1994)
tumor necrosis factor receptor superfamily, member 13B / 31410— at / AFO 23614 I NM— 012452 / NP一 036584 I Science 278 (5335) , 138-141 (1997) H2B histone family, member H I 31523一 f一 at / Z80780 I NM— 003523 / NP— 003 514 I - keratin, hair, acidic, 3A I 31594— at / Y16788 / NM— 004138 / NP一 004129 / Mol Biol Rep 1994-95 ;20 (3) : 155 - 61 tumor necrosis factor receptor superfamily, member 13B / 31410—at / AFO 23614 I NM—012452 / NP-1 036584 I Science 278 (5335), 138-141 (1997) H2B histone family, member HI 31523-1 f-1 at / Z80780 I NM— 003523 / NP— 003 514 I-keratin, hair, acidic, 3A I 31594—at / Y16788 / NM— 004138 / NP-004129 / Mol Biol Rep 1994-95; 20 (3): 155-61
37 kDa leucine— rich repeat (LRR) protein I 32057— at / U32907 I 00582 4 I NP_005815 / Biochim. Biophys. Acta 1309 (3) , 183-188 (1996) cholesterol 25- hydroxylase / 32363— at / AF059214 I 丽— 003956 I NP— 00394 7 / J. Biol. Chem. 273 (51) , 34316-34327 (1998)  37 kDa leucine— rich repeat (LRR) protein I 32057— at / U32907 I 00582 4 I NP_005815 / Biochim. Biophys. — 003956 I NP— 00394 7 / J. Biol. Chem. 273 (51), 34316-34327 (1998)
SMARCD3 I 32565— at / U66619 / 画一 003078 / NP— 003069 / Genes Dev. 10 (1 7) , 2117-2130 (1996) brain abundant, membrane attached signal protein 1 / 32606一 at / AA13568SMARCD3 I 32565—at / U66619 / uniform 003078 / NP— 003069 / Genes Dev. 10 (1 7), 2117-2130 (1996) brain abundant, membrane attached signal protein 1/32606 ichi at / AA13568
3 I L006317 / NP一 006308 / Mol Cells 1998 Aug 31 ;8 (4)： 471-7 3 I L006317 / NP-006308 / Mol Cells 1998 Aug 31; 8 (4): 471-7
brain abundant, membrane attached signal protein 1 / 32607一 at / AF03965brain abundant, membrane attached signal protein 1 / 32607-1 at / AF03965
6 I NM—006317 / NP一 006308 I Mol Cells 1998 Aug 31 ;8 (4) :471-7 6 I NM-006317 / NP-006308 I Mol Cells 1998 Aug 31; 8 (4): 471-7
SEC24 related gene family, member D (S. cerevisiae) / 32770— at / ABO 182 SEC24 related gene family, member D (S. cerevisiae) / 32770—at / ABO 182
98 I NM一 014822 / NP一 055637 / DNA Res. 5 (5)， 277-286 (1998) 98 I NM-1 014822 / NP 055637 / DNA Res. 5 (5), 277-286 (1998)
glutathione S— transferase M3 (brain) / 32798— at / AF043105 / NM— 000849glutathione S—transferase M3 (brain) / 32798—at / AF043105 / NM—000849
/ NP一 000840 I J Biol Chem 1990 Jun 5 ;265 (16) :9188-93 / NP-00080008 I J Biol Chem 1990 Jun 5; 265 (16): 9188-93
Friedreich ataxia I 33202_f— at / U43747 / NM— 000144 / NP一 000135 / Scien ce 1996 Mar 8 ; 271 (5254) : 1423 - 7  Friedreich ataxia I 33202_f—at / U43747 / NM—000144 / NP-000135 / Science 1996 Mar 8; 271 (5254): 1423-7
zinc finger protein 187 / 33220— at / Z11773 / l— 152736 / NP一 689949 / M ol Cell Biol 1992 May ; 12 (5) : 2432-43 zinc finger protein 187 / 33220—at / Z11773 / l—152736 / NP-689949 / Mol Cell Biol 1992 May; 12 (5): 2432-43
KIAA1095 protein / 33240— at / AB029018 / AB029018 / BAA83047 / DNA Res 1999 Jun 30 ;6 (3) : 197-205  KIAA1095 protein / 33240— at / AB029018 / AB029018 / BAA83047 / DNA Res 1999 Jun 30; 6 (3): 197-205
AREB6 I 33439— at / D15050 / NM— 030751 / NP— 110378 / J. Biochem. 114 (6)， 849-855 (1993)  AREB6 I 33439-at / D15050 / NM-030751 / NP-110378 / J. Biochem. 114 (6), 849-855 (1993)
MLLTIO I 33773— at / U13948 / NM— 004641 / NP一 004632 / Blood 85 (6) , 143 5-1441 (1995)  MLLTIO I 33773—at / U13948 / NM—004641 / NP-004632 / Blood 85 (6), 143 5-1441 (1995)
ESTs I 34093— at / AI829701 I AI829701 / - / - collagen, type XIV， alpha 1 (undulin) - / 34388— at / Y11710 / BCO 14640 / AAH14640 / - ESTs I 34093— at / AI829701 I AI829701 /-/-collagen, type XIV, alpha 1 (undulin)-/ 34388— at / Y11710 / BCO 14640 / AAH14640 /-
FLJ12280 I 34778— at / AA418080 / A 022342 I - I - amphiregulin (AR) / 34898— at / M30704 / 醒— 001657 / NP— 001648 I Mol. CeFLJ12280 I 34778— at / AA418080 / A 022342 I-I-amphiregulin (AR) / 34898 — at / M30704 / Awake — 001657 / NP — 001648 I Mol. Ce
11. Biol. 10 (5)， 1969-1981 (1990) 11. Biol. 10 (5), 1969-1981 (1990)
ESTs I 35007一 at / AC004940 / BF977449 I - I - molybdenum cofactor synthesis 3 I 35399— at / AF102544 I 丽— 014484 I NP一 055299 I - guanylate binding protein 1， interferon-inducible, 67kDa I 35735一 at / M 55542 I NM— 002053 I NP— 002044 / Mol. Cell. Biol. 11 (9) , 4717-4725 (199 1) ESTs I 35007 at / AC004940 / BF977449 I-I-molybdenum cofactor synthesis 3 I 35399— at / AF102544 I 丽 — 014484 I NP 055299 I-guanylate binding protein 1, interferon-inducible, 67kDa I 35735 at / M 55542 I NM— 002053 I NP— 002044 / Mol. Cell. Biol. 11 (9), 4717-4725 (199 1)
ras homolog gene family, member E I 35803— at / S82240 / NM一 005168 / NP一 005159 I MoL Cell. Biol. 16 (6) , 2689-2699 (1996) ras homolog gene family, member E I 35803— at / S82240 / NM-005168 / NP-005159 I MoL Cell. Biol. 16 (6), 2689-2699 (1996)
KIAA0924 I 35878— at / AB023141 / NM一 014897 / NP— 055712 / DNA Res. 6 (1) , 63-70 (1999)  KIAA0924 I 35878—at / AB023141 / NM 014897 / NP-055712 / DNA Res. 6 (1), 63-70 (1999)
armadillo repeat protein ALEX2 I 36057— at / AB011084 / L014782 / NP一 0armadillo repeat protein ALEX2 I 36057— at / AB011084 / L014782 / NP-1 0
55597 I Biochem. Biophys. Res. Coramun. 280 (1) , 340-347 (2001) 55597 I Biochem. Biophys. Res.Coramun. 280 (1), 340-347 (2001)
ETRIOI / 36097— at / M62831 I NM— 004907 / NP一 004898 / J. Biol. Chem. 266 ETRIOI / 36097—at / M62831 I NM—004907 / NP-004898 / J. Biol. Chem. 266
(19) , 12157-12161 (1991) (19), 12157-12161 (1991)
ΜΙΡ-1-alpha / 36103— at I D90144 / NM— 002983 / NP— 002974 / J. Biochem. 9 9 (3)， 885-894 (1986) ΜΙΡ-1-alpha / 36103—at I D90144 / NM—002983 / NP—002974 / J. Biochem. 99 (3), 885-894 (1986)
caspase 3, apoptos is - related cysteine protease (variant beta) / o6143_a t I U13737 I NM— 004346 / NP— 004337 / J. Biol. Chem. 269 (49)， 30761—307 64 (1994) caspase 3, apoptos is-related cysteine protease (variant beta) / o6143_at I U13737 I NM— 004346 / NP— 004337 / J. Biol. Chem. 269 (49), 30761—307 64 (1994)
caspase 3， apoptos is -： related cysteine protease (variant alpha) / ύθΐ43_ at I U13737 / NM一 032991 / NP— 116786 / J. Biol. Chem. 269 (49) , 30761-30 764 (1994) caspase 3, apoptos is-: related cysteine protease (variant alpha) / ύθΐ43_ at I U13737 / NM-032991 / NP— 116786 / J. Biol. Chem. 269 (49), 30761-30 764 (1994)
clone 23933 / 36234— at / U79273 I U79273 I - I - keratin, hair, acidic, 1 / 36310— at / X86570 / NM— 002277 / NP一 002268 I Biochim. Biophys. Acta 1264 (1) , 12—14 (1995) clone 23933 / 36234— at / U79273 I U79273 I-I-keratin, hair, acidic, 1 / 36310— at / X86570 / NM— 002277 / NP-002268 I Biochim. Biophys. Acta 1264 (1), 12—14 ( 1995)
BL34 regulator of G - protein signalling 1 I 36575— at / S59049 I 匪— 00292 BL34 regulator of G-protein signaling 1 I 36575— at / S59049 I Marauder— 00292
2 I NP— 002913 / J. Immunol. 150 (9) , 3895-3904 (1993) 2 I NP— 002913 / J. Immunol. 150 (9), 3895-3904 (1993)
Idl I 36618— g一 at / X77956 / 羅— 002165 / NP— 002156 / Biochim. Biophys. A cta 1219 (1) , 160-162 (1994) Idl I 36618-g at at / X77956 / Ra-002165 / NP-002156 / Biochim. Biophys. A cta 1219 (1), 160-162 (1994)
BTG2 / 36634— at / U72649 / NM— 006763 / NP_006754 / Nat. Genet. 14 (4) , 482-486 (1996)  BTG2 / 36634—at / U72649 / NM—006763 / NP_006754 / Nat.Genet. 14 (4), 482-486 (1996)
G0S3 Fos-B I 36669— at I L49169 / NM— 006732 / NP— 006723 / DNA Cell Biol. G0S3 Fos-B I 36669—at I L49169 / NM—006732 / NP—006723 / DNA Cell Biol.
15 (12) , 1025-1038 (1996) 15 (12), 1025-1038 (1996)
weel tyrosine kinase / 36909_at I X62048 / NM_003390 / NP_003381 / Natu re 353 (6339) , 80—83 (1991) weel tyrosine kinase / 36909_at I X62048 / NM_003390 / NP_003381 / Nature 353 (6339), 80-83 (1991)
glucose transporter-like protein - III (GLUT3) / 36979一 at / M20681 / NM— 0 06931 I NP— 008862 / J. Biol. Chem. 263 (30)， 15245-15248 (1988) glucose transporter-like protein-III (GLUT3) / 36979 at / M20681 / NM— 0 06931 I NP—008862 / J. Biol. Chem. 263 (30), 15245-15248 (1988)
YDD19 protein / 37079— at / U82319 / U82319 / AAB72234 / - GRO-beta / 37187— at / M36820 I NM— 002089 / NP— 002080 / Proc. Natl. Acad. Sci. U. S. A. 87 (19)， 7732 - 7736 (1990) YDD19 protein / 37079— at / U82319 / U82319 / AAB72234 /-GRO-beta / 37187— at / M36820 I NM — 002089 / NP — 002080 / Proc. Natl. Acad. Sci. USA 87 (19), 7732-7736 ( 1990)
serine (or cysteine) proteinase inhibitor, clade I (neuroserpin) , membe r 1 / 37259一 at / Z81326 / NM— 005025 I NP— 005016 / Genomics 40 (1) , 55 - 6 2 (1997) serine (or cysteine) proteinase inhibitor, clade I (neuroserpin), member 1/37259 at / Z81326 / NM—005025 I NP—005016 / Genomics 40 (1), 55-62 (1997)
GEM (GTP binding protein overexpressed in skeletal muscle) I 37279— at / U10550 I NM— 005261 / NP一 005252 / Science 265 (5169) , 241-244 (1994) HB15 CD83 / 37536— at / Z11697 I NM— 004233 / NP— 004224 / Blood 81 (2) , 4 54-461 (1993)  GEM (GTP binding protein overexpressed in skeletal muscle) I 37279— at / U10550 I NM— 005261 / NP 005252 / Science 265 (5169), 241-244 (1994) HB15 CD83 / 37536— at / Z11697 I NM— 004233 / NP— 004224 / Blood 81 (2), 4 54-461 (1993)
NOT I 37623— at / X75918 I - I - I - NOT I 37623— at / X75918 I-I-I-
CD95, FAS I 37643— at / X63717 / NM— 000043 / NP— 000034 / - CD69 I 37645— at / Z22576 / NM— 001781 / NP一 001772 / J. Exp. Med. 178 (2) , 537-547 (1993) CD95, FAS I 37643— at / X63717 / NM— 000043 / NP— 000034 /-CD69 I 37645— at / Z22576 / NM— 001781 / NP-001772 / J. Exp. Med. 178 (2), 537-547 ( (1993)
c-rayc oncogene / 37724_at / V00568 / 匪一 002467 / NP一 002458 / Nature 303c-rayc oncogene / 37724_at / V00568 / Bandai 002467 / NP 002458 / Nature 303
(5919)， 725-728 (1983) (5919), 725-728 (1983)
holocarboxylase synthetase / 37764— at / D87328 / NM_000411 / NP— 000402 / Nat. Genet. 8 (2) , 122-128 (1994) holocarboxylase synthetase / 37764—at / D87328 / NM_000411 / NP—000402 / Nat. Genet. 8 (2), 122-128 (1994)
zinc finger protein 337 I 37860_at / AL049942 / 丽ー 015655 / P_056470 / chromosorae condensation 1 / 37927一 at / X12654 / NM—001269 / NP一 001260 / Genes Dev. 1 (6) , 585—593 (1987) zinc finger protein 337 I 37860_at / AL049942 / 丽 015655 / P_056470 / chromosorae condensation 1/37927 ichi at / X12654 / NM-001269 / NP 001260 / Genes Dev. 1 (6), 585—593 (1987)
heparin-binding EGF- like growth factor / 38037— at / M60278 / NM— 001945 I NP一 001936 I Science 251 (4996) , 936 - 939 (1991) heparin-binding EGF- like growth factor / 38037—at / M60278 / NM— 001945 I NP-001936 I Science 251 (4996), 936-939 (1991)
dermatopontin / 38058— at / Z22865 / NM_001937 / NP— 001928 / Genomics 17dermatopontin / 38058—at / Z22865 / NM_001937 / NP—001928 / Genomics 17
(2) , 463-467 (1993) (2), 463-467 (1993)
SERPINEl I 38125— at / M14083 / NM— 000602 / NP— 000593 / J. Clin. Invest.SERPINEl I 38125—at / M14083 / NM—000602 / NP—000593 / J. Clin. Invest.
78 (6) , 1673-1680 (1986) 78 (6), 1673-1680 (1986)
interleukin 6 (interferon, beta 2) / 38299— at / X04430 / NM— 000600 / NP —000591 I Eur. J. Biochem. 159 (3) , 625-632 (1986) interleukin 6 (interferon, beta 2) / 38299—at / X04430 / NM—000600 / NP—000591 I Eur. J. Biochem. 159 (3), 625-632 (1986)
Prostagrandin D2 Synthetase 21kD (brain) / 38406—f— at / AI207842 / 一 / - I - zinc finger protein 36, C3H type-like 1 / 38740一 at / X79067 / NM一 004926 I NP一 004917 I DNA Cell Biol. 13 (5) , 449-459 (1994)  Prostagrandin D2 Synthetase 21kD (brain) / 38406-f- at / AI207842 / one /-I-zinc finger protein 36, C3H type-like 1/38740 one at / X79067 / NM one 004926 I NP one 004917 I DNA Cell Biol. 13 (5), 449-459 (1994)
CYR61 I 38772— at / Y11307 / NM一 001554 / NP— 001545 / Oncogene 14 (14) , 1 753-1757 (1997)  CYR61 I 38772—at / Y11307 / NM-001554 / NP—001545 / Oncogene 14 (14), 1 753-1757 (1997)
IgG Fc binding protein I 39014一 at / D84239 / NM— 003890 / NP一 003881 / J. Biol. Chem. 272 (24) , 15232-15241 (1997)  IgG Fc binding protein I 39014-at / D84239 / NM— 003890 / NP-003881 / J. Biol. Chem. 272 (24), 15232-15241 (1997)
protein phosphatase 5, catalytic subunit / 391一 at / X89416 /丽— 006247 I NP— 006238 I EMBO J. 13 (18)， 4278-4290 (1994) protein phosphatase 5, catalytic subunit / 391 at / X89416 / 丽 — 006247 I NP— 006238 I EMBO J. 13 (18), 4278-4290 (1994)
P311 protein I 39710一 at I U30521 I 丽— 004772 / NP一 004763 / Eur. J. Neur osci. 5 (6)， 614-623 (1993)  P311 protein I 39710 at I U30521 I 丽 — 004772 / NP 004763 / Eur. J. Neur osci. 5 (6), 614-623 (1993)
GADD45B (growth arrest and DNA - damage - inducible, beta) / 39822— s— at I A F078077 I NM— 015675 I NP— 056490 / Cell 95 (4) , 521-530 (1998) GADD45B (growth arrest and DNA-damage-inducible, beta) / 39822—s—at IA F078077 I NM— 015675 I NP— 056490 / Cell 95 (4), 521-530 (1998)
ADP-ribosylation factor-like 7 / 39829一 at / AB016811 / NM— 005737 / NP一 0 05728 I FEBS Lett. 456 (3) , 384-388 (1999) ADP-ribosylation factor-like 7/39829 at / AB016811 / NM— 005737 / NP 0 05728 I FEBS Lett. 456 (3), 384-388 (1999)
syntaxin 11 / 39857_at / AF044309 / NM一 003764 / NP一 003755 / Biochem. Bi ophys. Res. Commun. 245 (2) , 627-632 (1998) syntaxin 11 / 39857_at / AF044309 / NM-003764 / NP-003755 / Biochem. Biophys. Res.Commun. 245 (2), 627-632 (1998)
ZFP36 (zinc finger protein 36) / 40448— at / M92843 / NM— 003407 / NP一 003 398 / DM Cell Biol. 12 (1)， 73—88 (1993)  ZFP36 (zinc finger protein 36) / 40448—at / M92843 / NM—003407 / NP-003 398 / DM Cell Biol. 12 (1), 73-88 (1993)
NDRG family member 4 I 40500— at / AF007138 / NM— 020465 / NP— 065198 / Ge nomics 73 (1)， 86-97 (2001)  NDRG family member 4 I 40500—at / AF007138 / NM—020465 / NP—065198 / Ge nomics 73 (1), 86-97 (2001)
NDRG family member 4 / 40500一 at / / NM— 022910 / NP— 075061 / Genomics 73 (1) , 86-97 (2001)  NDRG family member 4/40500 ichi at / / NM— 022910 / NP— 075061 / Genomics 73 (1), 86-97 (2001)
APR (ATL - derived PMA- responsive gene) / 41048— at / D90070 / NM一 021127 / NP— 066950 I J. Virol. 64 (10) , 4632-4639 (1990)  APR (ATL-derived PMA-responsive gene) / 41048— at / D90070 / NM 021127 / NP — 066950 I J. Virol. 64 (10), 4632-4639 (1990)
T54 protein / 41102— at / U66359 I I I · T54 protein / 41102— at / U66359 I I I ·
A28-RGS14p / 41779— at / U70426 / NM— 002928 / NP— 002919 / Proc. Natl. Ac ad. Sci. U. S. A. 94 (15) , 7868—7872 (1997)  A28-RGS14p / 41779—at / U70426 / NM—002928 / NP—002919 / Proc.Natl.Ac ad.Sci.U.S.A. 94 (15), 7868—7872 (1997)
rearranged L-rayc fusion sequence / 41852— at / U22377 / NM— 012421 / NP一 0rearranged L-rayc fusion sequence / 41852— at / U22377 / NM— 012421 / NP-1 0
36553 I Oncogene 11 (12) , 2699—2704 (1995) 36553 I Oncogene 11 (12), 2699—2704 (1995)
clone 24790 / 41864_at / AF052181 / AF052181 /— /一 . clone 24790 / 41864_at / AF052181 / AF052181 /-/ one.
nuclear receptor subfamily 4， group A, member 2 / 547_s_at / S77154 I Nnuclear receptor subfamily 4, group A, member 2 / 547_s_at / S77154 I N
M— 006186 I NP一 006177 / Mol. Endocrinol. 8 (11) , 1583 - 1591 (1994) tumor necrosis factor alpha inducible protein A20 / 595一 at / M59465 I NM— 006186 I NP-006177 / Mol.Endocrinol. 8 (11), 1583-1591 (1994) tumor necrosis factor alpha inducible protein A20 / 595-at / M59465 I N
M— 006290 I NP— 006281 / J. Biol. Chem. 265 (25)， 14705-14708 (1990) beta - 2 - adrenergic receptor / 610一 at / M15169 /画一 000024 / NP— 000015 /M— 006290 I NP— 006281 / J. Biol. Chem. 265 (25), 14705-14708 (1990) beta-2-adrenergic receptor / 610 at / M15169 / uniform 000024 / NP— 000015
Proc. Natl. Acad. Sci. U. S. A. 84 (1) , 46-50 (1987) ' phosphodiesterase 3B I 746— at / D50640 / NM_000922 / NP— 000913 / Genomi cs 36 (3) , 476-485 (1996) Proc. Natl. Acad. Sci. USA 84 (1), 46-50 (1987) 'phosphodiesterase 3B I 746—at / D50640 / NM_000922 / NP—000913 / Genomi cs 36 (3), 476-485 (1996)
EGR1 (early growth response 1) / 789一 at / X52541 / NM_001964 / NP— 00195 5 / Nucleic Acids Res. 18 (14) , 4283 (1990)  EGR1 (early growth response 1) / 789 at / X52541 / NM_001964 / NP- 00195 5 / Nucleic Acids Res. 18 (14), 4283 (1990)
MCP1 I 875_g_at / M26683 / NM_002982 I NP— 002973 / FEBS Lett. 244 (2) , 487-493 (1989)  MCP1 I 875_g_at / M26683 / NM_002982 I NP— 002973 / FEBS Lett. 244 (2), 487-493 (1989)
〔実施例 4〕 ァトピー性皮膚炎患者の皮膚組織と乾癬患者の皮膚組織間での 遺伝子発現の比較  [Example 4] Comparison of gene expression between skin tissue of atopic dermatitis patient and skin tissue of psoriasis patient
代表的な 2つの炎症性皮膚疾患の炎症局所における遺伝子発現を比較するこ とにより、 アトピー性皮膚炎特異的な変動を示す遺伝子、 乾癬特異的な変動を 示す遺伝子、 両疾患で共通変動する遺伝子を同定することができる。 実施例 1 で選択された遺伝子群の中からァトピー性皮膚炎病態において特異的な発現変 動を示す遺伝子を選択することを目的に、 乾癬患者の皮膚組織における遺伝子 発現解析を行い、 アトピー性皮膚炎患者の皮膚組織における遺伝子発現解析結 果と比較した。  By comparing gene expression in the inflamed region of two representative inflammatory skin diseases, a gene showing a change specific to atopic dermatitis, a gene showing a change specific to psoriasis, and a gene showing a common change in both diseases Can be identified. In order to select a gene showing a specific expression change in atopic dermatitis pathological condition from the gene group selected in Example 1, gene expression analysis was performed on the skin tissue of a psoriasis patient. The results were compared with the results of gene expression analysis in skin tissue of inflamed patients.
乾癬患者 6例から同意を得て、 無瘆部と病変部を各部位からそれぞれ 3個の 皮膚検体 （直径 3mm) を採取した。  With consent from six patients with psoriasis, three skin specimens (3 mm in diameter) were collected from each of the arachnoid and lesioned areas.
ヒト皮膚からのジーンチップ解析用の RNA調製、 ジーンチップ用の cDNA合成、 DNAチップ解析は実施例 1に従つて行つた。  Preparation of RNA for gene chip analysis from human skin, cDNA synthesis for gene chip, and DNA chip analysis were performed according to Example 1.
ァトピー性皮膚炎患者と乾癬患者の無疹部と皮疹部間で発現変動する遺伝子群 の比較 Comparison of genes whose expression fluctuates between eruption and eruption in atopic dermatitis patients and psoriasis patients
6例の乾癬患者の無瘆部における遺伝子発現と皮疹部における遺伝子発現を C omparison analysis によって比較解析を行い、 無疹部と比べて皮疹部で 2倍以 上発現が増加している遺伝子、 1/2以下に発現が減少している遺伝子を選択した。 患者ごとに選んできた遺伝子について、 今度は 6例の患者のうち 4例以上で共 通変動している遺伝子を選択した。 これらの遺伝子群について、 Comparison an alysis後の Average Difference値を用いてウィルコクソン符号付順位和検定 (Wilcoxon signed- ranks test) を行い、 p値を算出した。 選択した遺伝子群と 実施例 1で行ったァトピー性皮膚炎患者の無疹部と皮疹部間の比較で発現変動 が認められた遺伝子群を比較することにより、 アトピー性皮膚炎と乾癬で共通 変動する遺伝子、 アトピー性皮膚炎でのみ発現変動を示す遺伝子、 乾癬でのみ 発現変動を示す遺伝子を同定した。 A comparative analysis of the gene expression in the abscess area and the rash area of 6 patients with psoriasis was performed by Comparison analysis, and the genes whose expression was more than 2-fold higher in the rash area than in the rash area, 1 A gene whose expression decreased to less than / 2 was selected. Of the genes selected for each patient, we now select genes that are commonly fluctuating in four or more of the six patients. For these genes, Wilcoxon signed rank sum test was performed using the Average Difference value after Comparison analysis. (Wilcoxon signed-ranks test) was performed to calculate the p-value. By comparing the selected gene group and the gene group whose expression was found to be different between the eruption area and the eruption area of atopic dermatitis patients performed in Example 1, common fluctuation was observed in atopic dermatitis and psoriasis Genes whose expression was altered only in atopic dermatitis and genes whose expression was altered only in psoriasis were identified.
ァトピー性皮膚炎と乾癬で共通変動した遺伝子群を表 2 5〜表 3 8に、 アト ピー性皮膚炎でのみ発現変動を示した遺伝子群を表 3 9〜表 5 2に、 乾癬での み発現変動を示した遺伝子群を表 5 3〜表 6 6に示した。  Tables 25-38 show the genes that fluctuated commonly in atopic dermatitis and psoriasis, and Tables 39-52 show genes that fluctuated only in atopic dermatitis. Tables 53 to 66 show the gene groups showing the expression fluctuation.
表 2 5  Table 25
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間で、 共通 変動 （増加） した遺伝子を示した。 表中に記載されている、 ΐ † † ΐは変動が 5 0倍以上、 †† †は 10〜50倍、 ††は 3〜10倍、 †は 2〜3倍、 一は変動なしで あることを示す。 Genes that showed a common variation (increase) between atopic dermatitis (rash and rash) and psoriasis (rash and rash) were shown. In the table, 変 動 † † 変 動 has a change of 50 times or more, †† 10 is 10 to 50 times, †† is 3 to 10 times, † is 2 to 3 times, and 1 is no change It indicates that.
ΤΤΤί 50倍以上 1/50倍以下 ΤΤΤί 50 times or more 1/50 times or less
ίΤΤ 10- 50倍 1/50〜1/10倍  ίΤΤ 10-50 times 1 / 50〜1 / 10 times
ττ 3-10倍 a 1/10~l/3倍  ττ 3-10 times a 1/10 ~ l / 3 times
τ 2-3倍 ι 1/3〜1/2倍  τ 2-3 times ι 1 / 3〜1 / 2 times
変動なし  No change
表 N-1 :アトピー性皮膚炎と乾癬の患者皮膚組織で共通変動を示した遺伝子 Table N-1: Genes showing common variation in skin tissues of patients with atopic dermatitis and psoriasis
(無疹部に比べて皮疡部で発現量が増加していた遺伝子）  (A gene whose expression level was increased in the skin area compared to the non-rash area)
Increase (無疹部ぐ皮疹部） Increase (no rash, no rash)
Atopic Dermatitis Psoriasis  Atopic Dermatitis Psoriasis
case case  case case
Probe ID 2 3 4 6 9 10 12 13 15 16 17 P値 1 2 3 4 5 6 Ρ値 Accession Probe ID 2 3 4 6 9 10 12 13 15 16 17 P value 1 2 3 4 5 6 Ρ value Accession
Protease and associated molecule Protease and associated molecule
133— at T τ ίί ί τ ί ί ίίΐ Τί 0.003 ί τ ί τ 0.005 X87212  133-- at T τ ίί τ τ ί ί ίίΐ Τί 0.003 ί τ ί τ 0.005 X87212
31345 at ί ίΤ ί τ ίί 0.012 TT ίί ίίί ίί 0.011 AB002134 t 31345 at ί ίΤ τ τ ίί 0.012 TT ίί ίί ίί 0.011 AB002134 t
37137一 at Τί τ ίί ττ ίίί 0.018 ίί ττ τ ττ 0.058 17016 〇37 137 at Τί τ ίί ττ ίίί 0.018 τ ττ τ ττ 0.058 17016 〇
37554 at ίΐί ττ ίίί ί ί Τί Τί ίί ττ 0.007 TT ττ ίΐ ΤΤΤί ΠίΤ ΤίΤ 0.005 U62801 h-1 37554 at τ ττ ίίί ί Τί Τί Τί τ ττ 0.007 TT ττ ίΐ ΠίΤ ΤίΤ 5 0.005 U62801 h- 1
40043— at ί ί ττ τ τ Τί 0.003 T ί ίΤ ίί ί ί 0.001 X71345 40043— at ί ί ττ τ τ Τί 0.003 T ί ίΤ ίί ί ί 0.001 X71345
32821 at TT Τί ττ ίί ττ Τί 0.003 τττ ττ ΤΤί Τίΐ ττττ τττ 4Ε-04 AI762213 32821 at TT τ ττ ίί ττ Τί 0.003 τττ ττ ΤΤί Τίΐ ττττ τττ 4Ε-04 AI762213
Protease inhibitor Protease inhibitor
1343 s at ίΤ Τί ίίί ττ ττ ί ί τττ Τί τττ ττ 0.003 ΤΤί ίί T†T πτ ττττ ίίί 4Ε-04 S66896  1343 s at ίΤ Τί τ ττ ττ ί ί τττ Τί τττ ττ 0.003 ΤΤί ίί T † T πτ ττττ ίίί 4Ε-04 S66896
1549 s at ΤΐΤ ίΤί Τ1 Γίί ΤίΤΤ Τί ττ ττττ τττ ττττ ΤίΤΤ 0.003 ττττ ίί Τίΐΐ す ΤίΤ ΤΤίί ίΐ τく.0001 U19557  1549 s at ΤΐΤ ίΤί Τ1 Γίί ΤίΤΤ τ ττ ττττ τττ ττττ ΤίΤΤ 0.003 ττττ ίί Τίΐΐ ΤίΤ ΤίΤ ίΐ τ τoku.0001 U19557
33305 at T† ΐΐ τ ίί η η η η ττ ίί 0.003 ίί ΐ Τΐ ίΐ ίί ί1 く.0001 M93056  33305 at T † τ τ ίί η η η η ττ ίί 0.003 ίί ΐ Τΐ ίΐ ί ίί1 0001 M93056
36781 at τ ί τ ττ ΤΐΤ ττ 0.028 ίΐ ί τ 0.046 X01683  36781 at τ ί τ ττ ΤΐΤ ττ 0.028 ίΐ ί τ 0.046 X01683
41469— at ΤΤί πτ †TT ΐίί ττ τ τττ τπ ΤΐΤ Τίί 0.004 ττττ Τΐ ΤΤίί Τΐί ττττ ΐΐί 0001 L10343  41469-- at π πτ † TT ΐίί ττ τ τττ τπ ΤΐΤ Τίί 0.004 ττττ Τΐ ΤΤίί Τΐί ττττ ΐΐί 0001 L10343
Cytokine, Cytokine Receptor (Growth factorも含む)  Cytokine, Cytokine Receptor (including Growth factor)
36227一 at τ ίί Τί ττ ττ ττ ΤΐΤ ττ 0.003 ττ ττ ττ 0.027 AF043129 36 227 at τ ίί τ ττ ττ ττ ΤΐΤ ττ 0.003 ττ ττ ττ 0.027 AF043129
404 at ττ ττ ΐ ί τ ττ τ 0.003 τ τ τ τ 0.003 X52425 404 at ττ ττ ΐ ί τ ττ τ 0.003 τ τ τ τ 0.003 X52425
36879 at ΐί ίίί m ίί Τί τ Τί ίίΐ η ίίί IT 0.003 m τ τττ m ΐίίΐ τττ 1 Ε-04 M63193  36879 at ΐί ίίί m ίί τ τ Τί ίίΐ η ίίί IT 0.003 m τ τττ m ΐίίΐ τττ 1 Ε-04 M63193
33849 at ί ίΤ ί ττ τ it † 0.003 ίί † † ίί ίί ίΐ 0.001 U02020  33849 at ί ίΤ τ ττ τ it † 0.003 ίί † † ίί ίί ίΐ 0.001 U02020
Chemokine, Chemokine receptor Chemokine, Chemokine receptor
Figure imgf000203_0001
Figure imgf000203_0001
0 2 t 0 2 t
〇 〇
CO CO
Figure imgf000204_0001
Figure imgf000204_0001
≠ 7^ ≠ 7 ^
Figure imgf000205_0001
Figure imgf000205_0001
8 S挲 i 0 Z 8 S 挲 i 0 Z
808600/C00Zdf/X3d 98CTC0/tO0Z OAV 表 2 9 808600 / C00Zdf / X3d 98CTC0 / tO0Z OAV Table 29
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間で、 共通 変動 （増加） した遺伝子 （表 2 5〜表 2 8 ) の説明を示した。 The explanation of the genes (Tables 25 to 28) that showed a common variation (increase) between atopic dermatitis (no rash and rash) and psoriasis (no rash and no rash) was shown.
表 N- 1(D):アトピー性皮膚炎と乾癬の患者皮廣組織で共通変動を示した遺伝子 (無疹部に比べて皮疹部で発現量が増加していた遺伝子） increase Table N-1 (D): Genes that showed a common variation in the percutaneous tissue of patients with atopic dermatitis and psoriasis (genes whose expression level was increased in the rash area compared to the rash area) increase
AD PS  AD PS
Probe ID P値 P値 Accession Descriptions  Probe ID P value P value Accession Descriptions
Protease and associated molecule  Protease and associated molecule
133 at 0.003 0.005 X87212 cathepsin C  133 at 0.003 0.005 X87212 cathepsin C
31345 at 0.012 0.011 AB002134 airway trypsin-Iike protease  31345 at 0.012 0.011 AB002134 airway trypsin-Iike protease
37137 at 0.018 0.058 M17016 serine protease-like protein  37137 at 0.018 0.058 M17016 serine protease-like protein
37554 at 0.007 0.005 U62801 protease M  37554 at 0.007 0.005 U62801 protease M
40043— at 0.003 0.001 X71345 trypsinogen IV b-form  40043—at 0.003 0.001 X71345 trypsinogen IV b-form
32821 at 0,003 4E-04 AI762213 neutrophil gelatinase associated lipocalin  32821 at 0,003 4E-04 AI762213 neutrophil gelatinase associated lipocalin
Protease inhibitor  Protease inhibitor
1343 s at 0.003 4E-04 S66896 squamous cell carcinoma antigen=serine protease inhibitor  1343 s at 0.003 4E-04 S66896 squamous cell carcinoma antigen = serine protease inhibitor
1549 s at 0.003ぐ 0001 U 19557 squamous cell carcinoma antigen 2 (SCCA2) t 1549 s at 0.003 0001 U 19557 squamous cell carcinoma antigen 2 (SCCA2) t
33305 at 〇 33305 at 〇
0.003 0001 M93056 mononcyte/ neutrophil elastase inhibitor  0.003 0001 M93056 mononcyte / neutrophil elastase inhibitor
36781 at 0.028 0.046 X01683 alpha 1 -antitrypsin  36781 at 0.028 0.046 X01683 alpha 1 -antitrypsin
41469 at 0.004 く細 1 L10343 elafin  41469 at 0.004 Fine 1 L10343 elafin
Cytokine, Cytokine Receptor (Growt i factorも含む）  Cytokine, Cytokine Receptor (including Groti i factor)
36227 at 0.003 0.027 AF043129 interleukin-7 receptor  36227 at 0.003 0.027 AF043129 interleukin-7 receptor
404 at 0.003 0.003 X52425 interleukin 4 receptor  404 at 0.003 0.003 X52425 interleukin 4 receptor
36879 at 0.003 1E-04 63193 platelet-derived endothelial cell growth factor  36879 at 0.003 1E-04 63193 platelet-derived endothelial cell growth factor
33849 at 0.003 0.001 U02020 pre— B cell enhancing factor (PBEF)  33849 at 0.003 0.001 U02020 pre— B cell enhancing factor (PBEF)
Chemokine Chemokine receptor  Chemokine Chemokine receptor
32128 at 0.003 0.001 Y13710 alternative activated macrophage specific CC chemokine 1  32 128 at 0.003 0.001 Y13710 alternative activated macrophage specific CC chemokine 1
37149 s at 0.004 0.031 U95626 lactotransferrin  37149 s at 0.004 0.031 U95626 lactotransferrin
408 at 0.005 0.021 X54489 melanoma growth stimulatory activity (MGSA) / Gro a  408 at 0.005 0.021 X54489 melanoma growth stimulatory activity (MGSA) / Gro a
S100 family proteins ( small(10-14kDa) calcium binding protein )  S100 family proteins (small (10-14kDa) calcium binding protein)
34458 at 0.003 く 0001 AA586894 psoriasin (S100A7)  34458 at 0.003 0001 AA586894 psoriasin (S100A7)
41096 at 0.003 く扁 1 A1126134 MRP-8 (S100A8)  41096 at 0.003 Kuban 1 A1126134 MRP-8 (S100A8)
41471 at 0.003 0001 W72424 MRP-14(S100A9) 41471 at 0.003 0001 W72424 MRP-14 (S100A9)
2027_at 0.003 0.002 M87068 CaN19(S100A2) 2027_at 0.003 0.002 M87068 CaN19 (S100A2)
35726 at 0.003 4E-04 AI539439 CaN19(S100A2)  35726 at 0.003 4E-04 AI539439 CaN19 (S100A2)
Cell adhesion and Related molecule  Cell adhesion and Related molecule
160031 at 0.008 <.0001 X63629 p cadherin  160031 at 0.008 <.0001 X63629 p cadherin
33693 at 0.003 0.001 M76482 130-kD pemphigus vulgaris antigen / Desmoglein 3  33693 at 0.003 0.001 M76482 130-kD pemphigus vulgaris antigen / Desmoglein 3
39302 at 0.003 0.001 X56807 desmocollins type 2b  39302 at 0.003 0.001 X56807 desmocollins type 2b
CD antigen Immunoglobulin-like receptor  CD antigen Immunoglobulin-like receptor
266 s at 0.004 ぐ 0001 L33930 CD24 signal transducer  266 s at 0.004 g 0001 L33930 CD24 signal transducer
37890 at 0.003 2E-04 X69398 OA3 antigenic surface determinant / CD47  37890 at 0.003 2E-04 X69398 OA3 antigenic surface determinant / CD47
35926 s at 0.003 2E-04 AF004230 monocyte/ macrophage Ig— related receptor MIR-7 / CD85  35926 s at 0.003 2E-04 AF004230 monocyte / macrophage Ig—related receptor MIR-7 / CD85
Kinase and Phosp natase  Kinase and Phosp natase
t t
1402 at 0.003 1E-04 16038 lyn 1402 at 0.003 1E-04 16038 lyn
〇 〇
32916 at 0.003 4E-04 X54134 protein tyrosine phosphatase, receptor type, E isoform1,232916 at 0.003 4E-04 X54134 protein tyrosine phosphatase, receptor type, E isoform1,2
1 1
677 s at 0.003 0.003 J04430 tartrate— resistant acid phosphatase type 5 677 s at 0.003 0.003 J04430 tartrate-- resistant acid phosphatase type 5
Enzyme ( without protease, kinase, p losphatase )  Enzyme (without protease, kinase, p losphatase)
32363 at 0.005 0.048 AF059214 cholesterol 25 - hydroxylase  32363 at 0.005 0.048 AF059214 cholesterol 25-hydroxylase
32775 r at 0.003 8E-04 AB006746 Phospholipid scramblase 1  32775 r at 0.003 8E-04 AB006746 Phospholipid scramblase 1
34666 at 0.003 1 E-04 X07834 manganese superoxide dismutase (EC 1.15.1.1)  34666 at 0.003 1 E-04 X07834 manganese superoxide dismutase (EC 1.15.1.1)
37351 at 0.005 4E-04 X90858 uridine phosphorylase  37351 at 0.005 4E-04 X90858 uridine phosphorylase
37482 at 0.003 2E-04 U37100 aldose reductase-like peptide  37482 at 0.003 2E-04 U37100 aldose reductase-like peptide
38389 at 0.005 0.002 X04371 2',5' oligoadenylate synthetase isoform E16, E18  38389 at 0.005 0.002 X04371 2 ', 5' oligoadenylate synthetase isoform E16, E18
39263 at 0.003 0.005 M87434 2',5' oligoadenylate synthetase 2 isoform p69, p71  39263 at 0.003 0.005 M87434 2 ', 5' oligoadenylate synthetase 2 isoform p69, p71
40671一 g at 0.005 1 E-04 AI148772 l_一 kynureni门 s hydrolase  40671 one g at 0.005 1 E-04 AI148772 l_ one kynureni 门 s hydrolase
430 at 0.004 0.002 X00737 purine nucleoside phosphorylase (PNP; EG 2.4.2.1)  430 at 0.004 0.002 X00737 purine nucleoside phosphorylase (PNP; EG 2.4.2.1)
34491 at 0.005 0.006 AJ225089 2',5' oligoadenylate synthetase - like (59 kDa isoform)  34491 at 0.005 0.006 AJ225089 2 ', 5' oligoadenylate synthetase-like (59 kDa isoform)
Cytoskeletal structural protein, cytoskeleton associated protein  Cytoskeletal structural protein, cytoskeleton associated protein
34301 r at 0.003 1 E-04 Z19574 cytokeratin l 7  34301 r at 0.003 1 E-04 Z19574 cytokeratin l 7
39015 f at 0.003 ぐ 0001 L42611 keratin 6A  39015 f at 0.003 g 0001 L42611 keratin 6A
39016 r at 0.003 く.0001し 42611 keratin 6A  39016 r at 0.003 ku.0001 then 42611 keratin 6A
^30 37473 at 0.003く .0001 AF061812 keratin 16 ^ 30 37473 at 0.003ku .0001 AF061812 keratin 16
601 s at 0.003 2E-04 M28439 keratin 16  601 s at 0.003 2E-04 M28439 keratin 16
40571一 at 0.003 0.001 U90942 myosin VA (heavy polypeptide 12, myoxin)  40571 one at 0.003 0.001 U90942 myosin VA (heavy polypeptide 12, myoxin)
33546 at 0.003 5E-04 AI923984 Small proline- rich protein SPRK  33546 at 0.003 5E-04 AI923984 Small proline-rich protein SPRK
36734 at 0.003 〈細 1 M21302 small proline-rich protein 2A  36734 at 0.003 <fine 1 M21302 small proline-rich protein 2A
37160 at 0.003く.0001 M19888 small proline-rich protein 1B (cornifin)  37160 at 0.003 0001 M19888 small proline-rich protein 1B (cornifin)
36355 at 0.003 1E-04 13903 involucrin  36355 at 0.003 1E-04 13903 involucrin
Interferon-inducib e protein Interferon-inducib e protein
37014— at 0.004 0.011 M33882 . ' interferon-inducible protein p78 ( X1)  37014— at 0.004 0.011 M33882. 'Interferon-inducible protein p78 (X1)
1107 s at 0.006 0.008 M13755 interferon- induced 17 - kDa/15 - kDa protein  1107 s at 0.006 0.008 M13755 interferon- induced 17-kDa / 15-kDa protein
425 at 0.003 5E-04 X67325 p27, interferon— alpha— inducible protein 27  425 at 0.003 5E-04 X67325 p27, interferon— alpha— inducible protein 27
〇 〇
G-protein and related molecule ooG-protein and related molecule oo
41086 at 0.01 7E-04 AF060877 regulator of G-protein signalling 20 41086 at 0.01 7E-04 AF060877 regulator of G-protein signaling 20
「ranscription factor "Ranscription factor
33339_g_at 0.004 0.012 M97936 STAT1  33339_g_at 0.004 0.012 M97936 STAT1
Others Others
1945 at 0.003 0.001 M25753 cyclin B  1945 at 0.003 0.001 M25753 cyclin B
34736 at 0.003 0.003 M25753 cyclin B  34736 at 0.003 0.003 M25753 cyclin B
31862 at 0.033 5E-04 L20861 proto-oncogene (Wnt-5a)  31862 at 0.033 5E-04 L20861 proto-oncogene (Wnt-5a)
32464 at 0.003 2E-04 AF071216 beta defensin 2 (HBD2)  32464 at 0.003 2E-04 AF071216 beta defensin 2 (HBD2)
38116一 at 0.01 0.003 D14657 KIAA0101  38 116 one at 0.01 0.003 D14657 KIAA0101
31888 s at 0.003 0.003 AF001294 tumor suppressing subtransferable candidate 3 ( TSSC3 )  31888 s at 0.003 0.003 AF001294 tumor suppressing subtransferable candidate 3 (TSSC3)
38489 at 0.041 0.004 60047 heparin binding protein (HBp17) 1 FGF-BP1  38489 at 0.041 0.004 60047 heparin binding protein (HBp17) 1 FGF-BP1
35919 at 0.005 0.005 J05068 transcobalamin I  35919 at 0.005 0.005 J05068 transcobalamin I
1 表 3 2 One Table 3 2
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間で、 共通 変動 （減少） した遺伝子を示した。 表中に記載されている、 丄 丄 丄 は 1/50倍 以下、 は 1/50〜： 1/10倍、 1は 1/10〜1/3倍、 iは 1/3〜1/2倍、 一は 変動なしであることを示す。 Genes that showed a common variation (decrease) between atopic dermatitis (no rash and rash) and psoriasis (no rash and no rash) were shown. In the table, 丄 1 丄 is 1/50 times or less, 1/50 or more: 1/10 times, 1 is 1/10 to 1/3 times, i is 1/3 to 1/2 times , One indicates no change.
50倍以上 1/50倍以下 50 times or more 1/50 times or less
ίΤί 10-50倍 1/50〜1/10倍  ίΤί 10-50 times 1 / 50-1 / 10 times
Τί 3-10倍 U 1/10〜1/3倍  Τί 3-10 times U 1 / 10-1 / 3 times
2-3倍 1/3〜1/2倍  2-3 times 1/3 to 1/2 times
変動なし  No change
I I
Figure imgf000211_0001
Figure imgf000211_0001
Q 1
Figure imgf000212_0001
Q 1
Figure imgf000212_0001
Inhibin Inhibin
32149 at u u u 1 u u ii 11 0.004 4 u u ii 0.074 AA532495 32149 at u u u 1 u u ii 11 0.004 4 u u ii 0.074 AA532495
38545 at i 1 1 u ii ·!· ϋ 0.003 I u Ui 3E-04 M3168238545 at i 1 1 u ii !! ϋ 0.003 I u Ui 3E-04 M31682
Others Others
Membrane protein  Membrane protein
38469 at u i u u i u iU i 0.003 U I i Ul 0.003 M35252 38469 at u i u u i u iU i 0.003 U I i Ul 0.003 M35252
40775 at i Ϊ 1 i I u i 0.003 I u i 11 3E-04 AL02178640775 at i Ϊ 1 i I u i 0.003 I u i 11 3E-04 AL021786
33610 at ii u u u u u i 0.008 u ii u 1 ii 0.005 AL04997733610 at ii u u u u u i 0.008 u ii u 1 ii 0.005 AL049977
33611— g_at ii 1 u ii u Ui 0.003 i U u i i 11 3E-04 AL04997733611— g_at ii 1 u ii u Ui 0.003 i U u i i 11 3E-04 AL049977
35844 at i i i 1 i i u 0.003 I i u 0001 D79206 35844 at i i i 1 i i u 0.003 I i u 0001 D79206
41158 at u i u i i ii 0.003 i i i 0.002 M54927 41158 at u i u i i ii 0.003 i i i 0.002 M54927
Secreted protein Secreted protein
40657—に at ii 11 u i u u u 0.008 u i i u 0.068 H15814 40657—at ii 11 u i u u u 0.008 u i i u 0.068 H15814
40658 r at ii Ί Ί u ii ii u 0.004 u I i 11 0.049 D4537140658 r at ii Ί Ί u ii ii u 0.004 u I i 11 0.049 D45371
Others Others
325 s at Ϊ 1U ill i ii i 11 ii i 0.003 i ii u 0.018  325 s at Ϊ 1U ill i ii i 11 ii i 0.003 i ii u 0.018
41094 at i J* Ί* Ί i ii i u ii Ui i 0.003 I i u 0.016 Y10179 41094 at i J * Ί * Ί i ii i u ii Ui i 0.003 I i u 0.016 Y10179
35026 f at i u ii u i ii 1 ii u 0.003 i ii ii 0.004 X78932 35026 f at i u ii u i ii 1 ii u 0.003 i ii ii 0.004 X78932
31326 at ii ii 11 i u u I i 0.003 I ii u u Ui i 2E-04 AF005081 31326 at ii ii 11 i u u I i 0.003 I ii u u Ui i 2E-04 AF005081
32242 at i i u i i i ii I ii 0.003 ii i u u u 0.028 AL03834032242 at i i u i i i ii I ii 0.003 ii i u u u 0.028 AL038340
33007 at u u u 1 u ii ii Ui i 0.005 u i i ii i u 4E-04 AC00230233007 at u u u 1 u ii ii Ui i 0.005 u i i ii i u 4E-04 AC002302
37576 at i i 1 ί i u ii I 0.041 u i u u ii 0.003 U5296937576 at i i 1 ί i u ii I 0.041 u i u u ii 0.003 U52969
37630 at 1 u u u u u 0.021 i i i u 0.02 AL04917637630 at 1 u u u u u 0.021 i i i u 0.02 AL049176
38418 at 1 1 1 u i 1 0.003 I ii i i 2E-04 X5979838418 at 1 1 1 u i 1 0.003 I ii i i 2E-04 X59798
39382 at 1 1 i i i i u 0.004 i I i i 6E-04 ABO" 08939382 at 1 1 i i i i u 0.004 i I i i 6E-04 ABO "089
521 at a ii ii i ii ii u u 0.007 ii U 111 u ill 0.051 U07807 521 at a ii ii i ii ii u u u u 0.007 ii U 111 u ill 0.051 U07807
41688 at i u 1 u u i u I 0.006 i 1 u i u i 0.008 AI688299 41688 at i u 1 u u i u i 0.006 i 1 u i u i 0.008 AI688299
33690 at ii u u u u u u u u 0.003 ii 1 111 ii ii 2E-04 AL08019033690 at ii u u u u u u u u 0.003 ii 1 111 ii ii 2E-04 AL080190
34445 at Ϊ I 1 i u i 0.003 i 1 i i i く .0001 AB00794034445 at Ϊ I 1 i u i 0.003 i 1 i i i k .0001 AB007940
35454 at u 1 i i i u i u 1 0.003 i u I i u 0.008 AB00791935454 at u 1 i i i u i u 1 0.003 i u I i u 0.008 AB007919
35669 at I u II u 1 ii u 11 0.003 i i Ϊ i I u 8E-04 AB01453335669 at I u II u 1 ii u 11 0.003 i i Ϊ i I u 8E-04 AB014533
36069 at 1 Ϊ u 1 i 1 i 0.003 i i 1 2E-04 AB007925 36069 at 1 Ϊ u 1 i 1 i 0.003 i i 1 2E-04 AB007925
¾34 ¾34
tt
■ at 0.008 Ji ii 11 11 Jl 0.002 A隱 82 CO■ at 0.008 Ji ii 11 11 Jl 0.002 A Oki 82 CO
4l837.at 11 J II 0.003 i 1 1 1 lil 1E-04 M画 4l837.at 11 J II 0.003 i 1 1 1 lil 1E-04 M
¾35 表 3 6 ¾35 Table 3 6
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間で、 共通 変動 （減少） した遺伝子 （表 3 2〜表 3 5 ) の説明を示した。 The explanation of the genes (Tables 32 to 35) that showed a common variation (decrease) between atopic dermatitis (no rash and rash) and psoriasis (no rash and no rash) is shown.
表 N- 2(D):アトピー性皮膚炎と乾癬の患者皮廣組織で共通変動を示した遺伝子 (無疹部に比べて皮疹部で発現が低下していた遺伝子） Decrease Table N-2 (D): Genes that showed common fluctuations in the percutaneous tissues of patients with atopic dermatitis and psoriasis (genes whose expression was lower in the rash than in the rash) Decrease
AD PS  AD PS
Probe ID P値 P値 Accession Descriptions  Probe ID P value P value Accession Descriptions
Protease  Protease
246 at 0.003 0.003 M25629 kallikreinl  246 at 0.003 0.003 M25629 kallikreinl
Protease inhibitor  Protease inhibitor
33128 s at 0.008 0.001 W68521 cystatin E/M  33128 s at 0.008 0.001 W68521 cystatin E / M
819 at 0.008 0.083 U76456 tissue inhibitor of metalloproteinase 4  819 at 0.008 0.083 U76456 tissue inhibitor of metalloproteinase 4
Cell adhesion and related molecule  Cell adhesion and related molecule
37857一 at 0.004ぐ 0001 AL080188 KIAA1775 ( MT-protocadherin)  37857 one at 0.004g 0001 AL080188 KIAA1775 (MT-protocadherin)
Cytoskeletal structural protein, cytoskeleton associated protein  Cytoskeletal structural protein, cytoskeleton associated protein
35766 at 0.006 0.006 26326 keratin 18  35766 at 0.006 0.006 26326 keratin 18
40899 at 0.003 0.004 Y00503 keratin 19  40899 at 0.003 0.004 Y00503 keratin 19
37407_s— at 0.01 0.003 AF013570 smooth muscle myosin heavy chain 11 , isoform SM2  37407_s—at 0.01 0.003 AF013570 smooth muscle myosin heavy chain 11, isoform SM2
773 at 0.036 0.005 D10667 smooth muscle myosin heavy chain 11 , isoform SM2  773 at 0.036 0.005 D10667 smooth muscle myosin heavy chain 11, isoform SM2
35105 at 0.003 4E-04 AF045941 sciellin (SCEL)  35105 at 0.003 4E-04 AF045941 sciellin (SCEL)
39544 at 0.006 0.011 AB002351 KIAA0353 / desmuslin (intermediate filament protein)  39544 at 0.006 0.011 AB002351 KIAA0353 / desmuslin (intermediate filament protein)
34203 at 0.028 0.017 D17408 calponinl  34203 at 0.028 0.017 D17408 calponinl
Kinase and Phosphatase  Kinase and Phosphatase
40524 at 0.008 0.005 X79510 protein - tyrosine - phosphatase Dl  40524 at 0.008 0.005 X79510 protein-tyrosine-phosphatase Dl
Enzyme (without protease, kinase, phosphatase and alcohol dehydrogenase)  Enzyme (without protease, kinase, phosphatase and alcohol dehydrogenase)
1103 at 0.109 0.072 11567 angiogenin (RNase A family, 5)  1103 at 0.109 0.072 11567 angiogenin (RNase A family, 5)
32664 at 0.003 0.001 D37931 RNase 4  32664 at 0.003 0.001 D37931 RNase 4
35051 at 0.016 0.01 M57892 carbonic anhydrase isozyme VI (CA6)  35051 at 0.016 0.01 M57892 carbonic anhydrase isozyme VI (CA6)
36680 at 0.003 2E-04 M24895 amylase, alpha 2B; pancreatic  36680 at 0.003 2E-04 M24895 amylase, alpha 2B; pancreatic
39317 at 0.003 2E-04 D86324 C P-N-acetylneuraminic acid hydroxylase  39317 at 0.003 2E-04 D86324 C P-N-acetylneuraminic acid hydroxylase
41120 at 0.004 0.004 D14686 Aminomethyltransferase (glycine cleavage system protein T)  41120 at 0.004 0.004 D14686 Aminomethyltransferase (glycine cleavage system protein T)
37124 i at 0.01 1 0.009 J04813 Cytochrome P450, subfamily IIIA, polypeptide 5 37124 i at 0.01 1 0.009 J04813 Cytochrome P450, subfamily IIIA, polypeptide 5
37125 f at 0.008 0.002 J04813 Cytochrome P450, subfamily HIA, polypeptide 5 37125 f at 0.008 0.002 J04813 Cytochrome P450, subfamily HIA, polypeptide 5
Alcohol dehydrogenase  Alcohol dehydrogenase
35730一 at 0.003 0.016 X03350 alcohol dehydrogenase IB (class I), beta polypeptide  35730 one at 0.003 0.016 X03350 alcohol dehydrogenase IB (class I), beta polypeptide
Fatty acid metabo ism re ated molecule  Fatty acid metabo ism re ated molecule
35185 at 0.047 0.046 AJ002962 FABP7 ( fatty acid binding protein 7)  35185 at 0.047 0.046 AJ002962 FABP7 (fatty acid binding protein 7)
38430 at 0.004 0.061 AA128249 FABP4 ( Fatty acid Dind!ng protein 4)  38430 at 0.004 0.061 AA128249 FABP4 (Fatty acid Dind! Ng protein 4)
37191 at 0.004 0.017 D87463 KIAA0273 / phytanoyl-CoA hydroxylase interacting protein  37191 at 0.004 0.017 D87463 KIAA0273 / phytanoyl-CoA hydroxylase interacting protein
Apolipoprotein  Apolipoprotein
36681 at 0.01 0.001 J02611 , apolipoprotein D  36681 at 0.01 0.001 J02611, apolipoprotein D
608 at 0.008 0.003 12529 apolipoprotein E  608 at 0.008 0.003 12529 apolipoprotein E
Grobin  Grobin
38585 at 0.012 0.101 91036 hemoglobin, gamma A, gamma G  38585 at 0.012 0.101 91036 hemoglobin, gamma A, gamma G
31687 f at 0.003 0.005 M25079 hemoglobin, beta  31687 f at 0.003 0.005 M25079 hemoglobin, beta
36329 at 0.003 8E-04 U33147 mammaglobin 1  36329 at 0.003 8E-04 U33147 mammaglobin 1
41066 at 0.017 0.023 AF071219 mammaglobin 2  41066 at 0.017 0.023 AF071219 mammaglobin 2
32880 at 0.004 0.004 AW015055 secretoglobin, family ID, member 2  32880 at 0.004 0.004 AW015055 secretoglobin, family ID, member 2
Transcription factor and related molecule、 1 ranscriptional regulator protein )  Transcription factor and related molecule, 1 ranscriptional regulator protein)
36629 at 0.008 0.011 AI635895 delta sleep inducing peptide, immunoreactor  36629 at 0.008 0.011 AI635895 delta sleep inducing peptide, immunoreactor
39171 at 0.003 2E-04 W21787 beta— catenin - interacting protein ICAT  39171 at 0.003 2E-04 W21787 beta— catenin-interacting protein ICAT
40511 at 0.004 0.003 X58072 GATA3  40511 at 0.004 0.003 X58072 GATA3
41027 at 0.05 0.006 AF078096 forkhead/ winged helix-like transcription factor 7 (FKHL7)  41027 at 0.05 0.006 AF078096 forkhead / winged helix-like transcription factor 7 (FKHL7)
41536一 at 0.003 8E-04 AL022726 Inhibitor of DNA binding 4 ( ID4 )  41536 one at 0.003 8E-04 AL022726 Inhibitor of DNA binding 4 (ID4)
Inhibin  Inhibin
32149 at 0.004 0.074 AA532495 Beta-microseminoprotein isoform a (PSP94), isoform b (PSP57)  32149 at 0.004 0.074 AA532495 Beta-microseminoprotein isoform a (PSP94), isoform b (PSP57)
38545一 at 0.003 3E-04 M31682 testicular inhibin beta-B-subunit  38545 one at 0.003 3E-04 M31682 testicular inhibin beta-B-subunit
Others  Others
Membrane protein  Membrane protein
^ 73 38469 at 0.003 0.003 M35252 TM4SF3 ( transmembrane 4 superfamily member 3 ) ^ 73 38469 at 0.003 0.003 M35252 TM4SF3 (transmembrane 4 superfamily member 3)
40775— at 0.003 3E-04 AL021786 ITM2A ( integral membrane protein 2A )  40775—at 0.003 3E-04 AL021786 ITM2A (integral membrane protein 2A)
33610 at 0.008 0.005 AL049977 claudin 8  33610 at 0.008 0.005 AL049977 claudin 8
33611 g at 0.003 3E-04 AL049977 claudin 8  33611 g at 0.003 3E-04 AL049977 claudin 8
35844— at 0.003 <.0001 D79206 syndecan 4 (amphiglycan, ryudocan)  35844—at 0.003 <.0001 D79206 syndecan 4 (amphiglycan, ryudocan)
41158 at 0.003 0.002 M54927 proteolipid protein 1  41158 at 0.003 0.002 M54927 proteolipid protein 1
Secreted protein  Secreted protein
40657 r at 0.008 0.068 H15814 ap 1( adipose most abundant gene transcript 1)  40657 r at 0.008 0.068 H15814 ap 1 (adipose most abundant gene transcript 1)
40658 r at 0.004 0.049 D45371 ap 1( adipose most abundant gene transcript 1)  40658 r at 0.004 0.049 D45371 ap 1 (adipose most abundant gene transcript 1)
Others  Others
325 s at 0.003 0.018 prolactin-inducible protein  325 s at 0.003 0.018 prolactin-inducible protein
41094_at 0.003 0.016 Y10179 prolactin-inducible protein  41094_at 0.003 0.016 Y10179 prolactin-inducible protein
35026 f at 0.003 0.004 X78932 HZF9 D 35026 f at 0.003 0.004 X78932 HZF9 D
31326 at 0.003 2E-04 AF005081 skin-specific protein (xp32) 31326 at 0.003 2E-04 AF005081 skin-specific protein (xp32)
- 3 -3
32242 at 0.003 0.028 AL038340 Crystallin, alpha B 32242 at 0.003 0.028 AL038340 Crystallin, alpha B
33007 at 0.005 4E-04 AC002302 Hepatocellular carcinoma antigen gene 520  33007 at 0.005 4E-04 AC002302 Hepatocellular carcinoma antigen gene 520
37576 at 0.041 0.003 U52969 Purkinje cell protein 4 (PCP4)  37576 at 0.041 0.003 U52969 Purkinje cell protein 4 (PCP4)
37630— at 0.021 0.02 AL049176 141H5  37630—at 0.021 0.02 AL049176 141H5
38418 at 0.003 2E-04 X59798 cyclin D1  38418 at 0.003 2E-04 X59798 cyclin D1
39382 at 0.004 6E-04 AB011089 TRIM2 ( tripartite motif-containing 2 )  39382 at 0.004 6E-04 AB011089 TRIM2 (tripartite motif-containing 2)
521 at 0.007 0.051 U07807 metallothionein IV (MTIV)  521 at 0.007 0.051 U07807 metallothionein IV (MTIV)
41688— at 0.006 0.008 A画 299 transmembrane 4 superfamily member 11 (plasmolipin)  41688—at 0.006 0.008 A painting 299 transmembrane 4 superfamily member 11 (plasmolipin)
33690 at 0.003 2E-04 AL080190 DKFZP434A202 33690 at 0.003 2E-04 AL080190 DKFZ P 434A202
34445一 at 0.003 〈扇 1 AB007940 瞧 0471  34445 one at 0.003 <Fan 1 AB007940 瞧 0471
35454 at 0.003 0.008 AB007919 KIAA0450  35454 at 0.003 0.008 AB007919 KIAA0450
35669 at 0.003 8E-04 AB014533 KIAA0633  35669 at 0.003 8E-04 AB014533 KIAA0633
36069— at 0.003 2E-04 AB007925 隠 0456  36069—at 0.003 2E-04 AB007925 Hidden 0456
41679 at 0.008 0.002 AF035282 C1orf21  41679 at 0.008 0.002 AF035282 C1orf21
41837 at 0.003 1 E-04 AA149431 DKFZp761F2014  41837 at 0.003 1 E-04 AA149431 DKFZp761F2014
^38 表 3 9 ^ 38 Table 3 9
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間の比較で、 アトピー性皮膚炎の皮疹部でのみ発現変動 （増加） した遺伝子を示した。 表中 記載されている、 T† ††は変動が 50倍以上、 †††は 10〜50倍、 † †は 3 '10倍、 †は 2〜3倍、 一は変動なしであることを示す。 A comparison between atopic dermatitis (no rash and rash) and psoriasis (no rash and no rash) showed genes whose expression was altered (increased) only in the rash of atopic dermatitis. In the table, T † †† indicates that the change is 50 times or more, ††† is 10 to 50 times, † 3 is 3'10 times, † is 2 to 3 times, and 1 is no change. Show.
ττττ 50倍以上 1/50倍以下 ίίί 10-50倍 1/50〜1/10倍 ίί 3-10倍 11 1/10〜1/3倍 2-3倍 1/3~1/2倍 変動なし ττττ 50 times or more 1/50 times or less ίίί 10-50 times 1 / 50-1 / 10 times ίί 3-10 times 11 1 / 10-1 / 3 times 2-3 times 1 / 3-1 / 2 times No change
1 1
Figure imgf000220_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000222_0001
32598 at ί 1 ίί ίί ί 1 it ίί ίί 0.003 .1 0.325 D83018 32598 at ί 1 ίί ίί ί 1 it ίί ίί 0.003 .1 0.325 D83018
32607— at ί ί ί ί ίί 0.003 0.244 AF039656  32607—at ί ί ί ί ίί 0.003 0.244 AF039656
36070— at ίί す ί ί ίί ίίί ίί ίί ΐί 0.008 ί ί ί 0.067 Αし 049389  36070— at ίί ίί ί ί ίί ίίί ίί ίί ίί ΐί 0.008 ί ί ί 0.067 Α 049389
37759 at ίί † ί ί ίί ί † 0.003 0.036 U51240  37759 at ίί † ί ί ί ίί ί 3 0.003 0.036 U51240
39862 at ίί π ί ίί ίί ίί 0.01 ίί ίί 0.024 ΑΑ528252  39862 at π π ί ίί ίί ίί 0.01 ίί ίί 0.024 ΑΑ528252
33272 at ίί ίί † ί 1 ίί ίί 0.006 ίί す ί ίί ί 0.745 ΑΑ829286  33272 at ίί ίί † ί 1 ίί ίί 0.006 ίί ί ίί ίί ί 0.745 ΑΑ829286
38363 at ί ίί ί ίί ί 0.003 0.086 W60864  38363 at ί ίί ί ίί ί 0.003 0.086 W60864
39799_at ί ίί ί ί ί ίί ί ί ίί ί 0.003 ί ί 5Ε-04 Μ94856  39799_at ί ίί ί ί ί ίί ί ίί ί ί 3 0.003 ί ί 5Ε-04 Μ94856
39591 s at ίί ί ί ίί ί 0.041 0.68 Ζ36531  39591 s at ίί ί ί ί ί 41 0.041 0.68 Ζ36531
40297_at ίί ίί † 0.003 0.73 AC005053  40297_at ίί ίί † 0.003 0.73 AC005053
^4 ^ 4
22一 表 4 3 22 one Table 4 3
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間の比較で- アトピー性皮膚炎の皮疹部でのみ発現変動 （増加） した遺伝子 （表 3 9〜表 4 2 ) の説明を示した。 Comparison between atopic dermatitis (no rash and rash) and psoriasis (no rash and no rash)-Genes whose expression was changed (increased) only in the rash of atopic dermatitis (Table 39-Table 4) 2) was explained.
表 O- 1 (D) :アトピー性皮膚炎と乾癬患者の皮膚組織における遺伝子発現を比較した結果、アトピ- -性皮膚炎患者の皮膚組織でのみ 発現変動が認められた遺伝子 Table O-1 (D): Comparison of gene expression in skin tissues of patients with atopic dermatitis and psoriasis.
Increase  Increase
AD PS  AD PS
Probe ID P値 P値 Accession Descriptions  Probe ID P value P value Accession Descriptions
Protease and associated molecule  Protease and associated molecule
1481一 at 0.006 0.149 L23808 metalloproteinase (HME)  1481 at 0.006 0.149 L23808 metalloproteinase (HME)
1482— g at 0.01 0.1 13 し 23808 metalloproteinase (HME)  1482—g at 0.01 0.1 13 s 23808 metalloproteinase (HME)
31859 at 0.004 0.03 J05070 type IV collagenase  31859 at 0.004 0.03 J05070 type IV collagenase
32514 s at 0.005 0.006 AF032906 cathepsin Z precursor (CTSZ)  32514 s at 0.005 0.006 AF032906 cathepsin Z precursor (CTSZ)
34974 at 0.012 0.589 Y13323 disintegrin-protease  34974 at 0.012 0.589 Y13323 disintegrin-protease
37391 at 0.003 0.052 X12451 ' pro- cathepsin L (major excreted protein MEP)  37391 at 0.003 0.052 X12451 'pro- cathepsin L (major excreted protein MEP)
38428 at 0.003 0.363 M 13509 skin collagenase  38428 at 0.003 0.363 M 13509 skin collagenase
40078 at 0.004 0.073 AF015287 SPUVE ( protease, serine, 23 )  40078 at 0.004 0.073 AF015287 SPUVE (protease, serine, 23)
40649 at 0.005 0.324 X64810 Proprotein convertase subtilisin/kexin typel  40649 at 0.005 0.324 X64810 Proprotein convertase subtilisin / kexin typel
Protease inhibitor  Protease inhibitor
1693 s at 0.003 0.908 D11139 tissue inhibitor of metalloproteinases  1693 s at 0.003 0.908 D11139 tissue inhibitor of metalloproteinases
38125 at 0.004 0.398 M 14083 beta-migrating plasminogen activator inhibitor I  38 125 at 0.004 0.398 M 14083 beta-migrating plasminogen activator inhibitor I
Cytokine, Cytokine Receptor (Growt i factorも含む）  Cytokine, Cytokine Receptor (including Groti i factor)
359 at 0.003 く扁 1 Y10659 IL-13Ra1  359 at 0.003 Kuban 1 Y10659 IL-13Ra1
38299 at 0.012 0.363 X04430 IFN-beta 2a ( IL-6 )  38299 at 0.012 0.363 X04430 IFN-beta 2a (IL-6)
38037 at 0.005 0.085 M60278 heparin - binding EGF-like growth factor  38037 at 0.005 0.085 M60278 heparin-binding EGF-like growth factor
37493 at 0.004 0.07 H04668 GM-CSFR beta  37493 at 0.004 0.07 H04668 GM-CSFR beta
Chemokine Chemokine receptor  Chemokine Chemokine receptor
1369 s at 0.018 0.194 M28130 interleukin 8 (IL8)  1369 s at 0.018 0.194 M28130 interleukin 8 (IL8)
34375 at 0.003 0.17 M28225 MCP-1  34375 at 0.003 0.17 M28225 MCP-1
875— g at 0.003 0.169 M26683 CP-1  875— g at 0.003 0.169 M26683 CP-1
36067 at 0.003 0.257 AB000887 EBIHigand chemokine  36067 at 0.003 0.257 AB000887 EBIHigand chemokine
36503 at 0.016 0.56 AB002409 SLC  36503 at 0.016 0.56 AB002409 SLC
37187 at 0.003 0.003 M36820 GRO-beta  37187 at 0.003 0.003 M36820 GRO-beta
37823 at 0.011 0.252 Y16645 monocyte chemotactic protein-2  37823 at 0.011 0.252 Y16645 monocyte chemotactic protein-2
^ 2 39994 at 0.013 0.312 D10925 CCR1 ^ 2 39994 at 0.013 0.312 D10925 CCR1
Cell adhesion and Related molecule  Cell adhesion and Related molecule
245— at 0.004 0.342 M25280 lymph node homing receptor / L-selectin  245—at 0.004 0.342 M25280 lymph node homing receptor / L-selectin
265 s at 0.003 0.087 M24736 endothelial leukocyte adhesion molecule 1 (ELAM-1)  265 s at 0.003 0.087 M24736 endothelial leukocyte adhesion molecule 1 (ELAM-1)
37918 at 0.008 0.046 M15395 leukocyte adhesion protein (LFA-1 /Mac-1 / 150,95 family) beta  37918 at 0.008 0.046 M15395 leukocyte adhesion protein (LFA-1 / Mac-1 / 150,95 family) beta
1372 at 0.003 0.715 M31165 TNFAIP6 ( tumor necrosis factor, alpha-induced protein 6 )  1372 at 0.003 0.715 M31165 TNFAIP6 (tumor necrosis factor, alpha-induced protein 6)
CD antigen, Immunoglobulin-like receptor  CD antigen, Immunoglobulin-like receptor
31438 s at 0.003 0.533 Z22971 M130 antigen extracellular variant / CD 163  31438 s at 0.003 0.533 Z22971 M130 antigen extracellular variant / CD 163
38378 at 0.006 0.113 M37033 CD 53 glycoprotein  38378 at 0.006 0.113 M37033 CD 53 glycoprotein
40518— at 0.003 0.017 Y00062 ■ T200 leukocyte common antigen (CD45, LC-A) isoform 1-3  40518—at 0.003 0.017 Y00062T200 leukocyte common antigen (CD45, LC-A) isoform 1-3
40519 at 0.013 0.222 Y00638 T200 leukocyte common antigen (CD45, LC-A) isoform 1—3  40519 at 0.013 0.222 Y00638 T200 leukocyte common antigen (CD45, LC-A) isoform 1-3
39395 at 0.003 0.053 AA704137 THY-1 (CD90)  39395 at 0.003 0.053 AA704137 THY-1 (CD90)
37148 at 0.015 0.278 AF025533 leucocyte immunoglobulin-like receptor - 3 (UR-3) t to ai 37148 at 0.015 0.278 AF025533 leucocyte immunoglobulin-like receptor-3 (UR-3) t to ai
Extracellular matrix protein Extracellular matrix protein
32818 at 0.003 0.238 X78565 tenascin-C  32818 at 0.003 0.238 X78565 tenascin-C
38427 at 0.003 0.025 L25286 alpha— 1 type XV collagen  38427 at 0.003 0.025 L25286 alpha— 1 type XV collagen
40162 s at 0.155 0.954 AC003107 cartilage oligomeric matrix protein ( COMP )  40162 s at 0.155 0.954 AC003107 cartilage oligomeric matrix protein (COMP)
32227 at 0.003 0.06 X17042 proteoglycan 1  32227 at 0.003 0.06 X17042 proteoglycan 1
Immunoglobulin, Immunoglobulin rece ptor, and related molecule  Immunoglobulin, Immunoglobulin receptor, and related molecule
33273 f at 0.047 0.163 X57809 immunoglobulin lambda light chain  33273 f at 0.047 0.163 X57809 immunoglobulin lambda light chain
33274 f at 0.041 0.25 18645 immunoglobulin lambda light chain  33274 f at 0.041 0.25 18645 immunoglobulin lambda light chain
36889 at 0.003 0.402 33195 Fc - epsilon - receptor gamma-chain  36889 at 0.003 0.402 33195 Fc-epsilon-receptor gamma-chain
37688 f at 0.005 0.382 M31932 IgG low affinity Fc fragment receptor (CD32)  37688 f at 0.005 0.382 M31932 IgG low affinity Fc fragment receptor (CD32)
37864 s at 0.093 0.255 Y14737 immunoglobulin heavy constant gamma 3 (G3m marker)  37864 s at 0.093 0.255 Y14737 immunoglobulin heavy constant gamma 3 (G3m marker)
38194 s at 0.026 0.207 M63438 immunoglobulin kappa constant  38194 s at 0.026 0.207 M63438 immunoglobulin kappa constant
41827 f at 0.069 0.124 AI932613 immunoglobulin lambda light chain  41827 f at 0.069 0.124 AI932613 immunoglobulin lambda light chain
Kinase and Phosp latase  Kinase and Phosp latase
2045 s at 0.003 0.856 16592 hemopoietic cell protein-tyrosine kinase (HCK)  2045 s at 0.003 0.856 16592 hemopoietic cell protein-tyrosine kinase (HCK)
35694 at 0.003 4E-04 AB014587 KIAA0687 1 MAP4K4  35694 at 0.003 4E-04 AB014587 KIAA0687 1 MAP4K4
^44
Figure imgf000227_0001
^ 44
Figure imgf000227_0001
9 拏  9 Halla
-— I  -— I
9 Z Z  9 Z Z
808600/f00Zdf/13d 98CTC0/tO0Z OAV 808600 / f00Zdf / 13d 98CTC0 / tO0Z OAV
39799 at 0.003 5E-04 M94856 fatty acid binding protein homologue (PA-FABP)39799 at 0.003 5E-04 M94856 fatty acid binding protein homologue (PA-FABP)
39591 s at 0.041 0.68 Z36531 fibrinogen-like 2 39591 s at 0.041 0.68 Z36531 fibrinogen-like 2
40297— at 0.003 0.73 AC005053 six transmembrane epithelial antigen of the prostate (STEAP) 40297—at 0.003 0.73 AC005053 six transmembrane epithelial antigen of the prostate (STEAP)
表 4 7 Table 4 7
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間の比較で, アトピー性皮膚炎の皮疹部でのみ発現変動 （減少） した遺伝子を示した。 表中 に記載されている、 丄 丄 丄は 1/50倍以下、 丄 i 丄は 1/50〜1/10倍、 丄 丄は 1 /10〜1/3倍、 は 1/3〜1/2倍、 一は変動なしであることを示す。 A comparison between atopic dermatitis (no rash and rash) and psoriasis (no rash and no rash) showed a gene whose expression was altered (decreased) only in the rash of atopic dermatitis. In the table, 丄 1 丄 is 1/50 or less, 丄 i 1 is 1/50 to 1/10, 丄 1 is 1/10 to 1/3, and 1/3 to 1 / Double, one indicates no change.
ΤίΤί 50倍以上 丄 1/50倍以下 ίίί 10-50倍 1/50~1/10倍 ίΐ 3- 10倍 u 1/10~1/3倍 ί 2-3倍 1 1/3~1/2倍 変動なし ΤίΤί 50 times or more 丄 1/50 times or less ίίί 10-50 times 1/50 to 1/10 times ίΐ 3 to 10 times u 1/10 to 1/3 times ί 2-3 times 1 1/3 to 1/2 No change
Figure imgf000230_0001
Figure imgf000230_0001
38927 i at u u I u I i ii 0.016 0.579 M27160 38927 i at u u I u I i ii 0.016 0.579 M27160
41771 g at l u u 1 i 1 i 0.006 i Ϊ 0.034 AA420624  41 771 g at l u u 1 i 1 i 0.006 i Ϊ 0.034 AA420624
41790 at Ϊ i 1 i 1 u 0.003 0.106 AL031230  41790 at Ϊ i 1 i 1 u 0.003 0.106 AL031230
Alcohol dehydrogenase  Alcohol dehydrogenase
34637 f at a u u i 1 u u 0.003 U i ii 0.02 M12963  34637 f at a u u i 1 u u 0.003 U i ii 0.02 M12963
36247— f— at u u u ii u 1 ii u Ui 0.018 M12272  36247— f— at u u u ii u 1 ii u Ui 0.018 M12272
Fatty acid metabolism relatec molecule  Fatty acid metabolism relatec molecule
33337 at Ϊ 1 i i 4 I 0.004 0.001 AF002668  33337 at Ϊ 1 i i 4 I 0.004 0.001 AF002668
35834 at u i Ϊ Ϊ ii u i Ui 0.016 4E-04 X59766  35834 at u i Ϊ ii ii u i Ui 0.016 4E-04 X59766
37122 at i i U ί u 1 il u 0.003 u 1 u 0.08 AB005293  37122 at i i U ί u 1 il u 0.003 u 1 u 0.08 AB005293
41209 at i u U u ii u u 0.01 u i 0.151 M15856  41209 at i u U u ii u u 0.01 u i 0.151 M15856
40409 at u u i ii u 11 i u 0.003 I i i 0.004 U46689  40409 at u u i ii u 11 i u 0.003 I i i 0.004 U46689
t t
Grobin COGrobin CO
31525— s— at il 11 - i | i i U i U _ i 0.003 一 一 i U — i 0.017 J00153 〇 31525— s—at il 11-i | i i U i U _ i 0.003 1 i u — i 0.017 J00153 〇
Transcription fac tor and related molecule (Transcriptional regulator protein ) Transcription fac tor and related molecule (Transcriptional regulator protein)
37809 at J- Ί 1 > i i 1 u ii 0.036 U 0.102 U41813  37809 at J- Ί 1> i i 1 u ii 0.036 U 0.102 U41813
39681 at U 11 u 1 u Ui 11 u u 0.008 ii U u u 0.168 AF060568  39681 at U 11 u 1 u Ui 11 u u 0.008 ii U u u 0.168 AF060568
Ion channe  Ion channe
37529 at 11 Ϊ 1 u ii 0.075 0.35 AF051946  37529 at 11 Ϊ 1 u ii 0.075 0.35 AF051946
39682 at U u u U ii u 0.004 u 0.575 X87159  39682 at U u u U ii u 0.004 u 0.575 X87159
Others  Others
Membrane protein  Membrane protein
34800 at i i i i I i i I u 0.004 i 0.002 AL039458  34800 at i i i i I i i I u 0.004 i 0.002 AL039458
35164 at u u ii u u u iU 0.028 111 U u 0.119 AF084481  35164 at u u ii u u u iU 0.028 111 U u 0.119 AF084481
38821 at u I Ϊ i i u 0.003 i I 5E-04 AJ002030  38821 at u I Ϊ i i u 0.003 i I 5E-04 AJ002030
34412 s at i u u u i 0.091 1 0.548 U59632  34412 s at i u u u i 0.091 1 0.548 U59632
37983 at a ii u i u u u 0.006 i i 1 0.023 S77410  37983 at a ii u i u u u 0.006 i i 1 0.023 S77410
39930 at u i u 11 1 0.01 i 0.006 D83492  39930 at u i u 11 1 0.01 i 0.006 D83492
0 s^ 0 s ^
Secreted protein Secreted protein
33975 at u 1 u u u I 0.18 u 0.363 S55606  33975 at u 1 u u u I 0.18 u 0.363 S55606
36024一 at II U I 1 i 0.017 u 11 0.066 S79048  36024 one at II U I 1 i 0.017 u 11 0.066 S79048
Others  Others
CO  CO
32552 at 1 u ii u I u 11 0.006 1 u I 0.182 X00129  32552 at 1 u ii u I u 11 0.006 1 u I 0.182 X00129
33332一 at 111 11 u u 11 i "ii 1U 0.18 Z93241  33332 one at 111 11 u u 11 i "ii 1U 0.18 Z93241
38851 at i u 1 ill 11 1 IU 0.003 1 1 0.008 M63394  38851 at i u 1 ill 11 1 IU 0.003 1 1 0.008 M63394
40017 at 11 1U u 11 u 111 0.013 11 u 0.084 AL050214  40017 at 11 1U u 11 u 111 0.013 11 u 0.084 AL050214
35579 at 1 1 1 II I 1 11 1 0.003 0.02 AB014524  35579 at 1 1 1 II I 1 11 1 0.003 0.02 AB014524
39577 at 1 1 I 1 1 u 0.004 0.046 AL050024  39577 at 1 1 I 1 1 u 0.004 0.046 AL050024
39625 at 1 11 II 1 I 0.003 0.004 AL050204  39625 at 1 11 II 1 I 0.003 0.004 AL050204
姍 49 表 5 0 姍 49 Table 50
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間の比較で, アトピー性皮膚炎の皮疹部でのみ発現変動 （減少） した遺伝子 （表 4 7〜表 4 9 ) の説明を示した。 In the comparison between atopic dermatitis (no rash and rash) and psoriasis (no rash and no rash), genes whose expression was changed (decreased) only in the rash of atopic dermatitis (Tables 47 to 4) 9) was explained.
表 0- 2(D) :アトピー性皮膚炎と乾癬患者の皮膚組織における遺伝子発現を比較した結果、アトピー性皮膚炎患者の皮膚組織でのみ 発現変動が認められた遺伝子 Table 0-2 (D): Gene expression in atopic dermatitis patients whose skin expression was fluctuated only in skin tissues of patients with atopic dermatitis as a result of comparing gene expression in skin tissues of patients with psoriasis
Decrease  Decrease
AD PS  AD PS
Probe ID P値 P値 Accession Descriptions  Probe ID P value P value Accession Descriptions
Protease  Protease
40717 at 0.062 0.004 AB001928 cathepsin V  40717 at 0.062 0.004 AB001928 cathepsin V
Protease inhibitor  Protease inhibitor
35577 at 0.026 0.064 AF027866 SERPINB7 (serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 7)  35577 at 0.026 0.064 AF027866 SERPINB7 (serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 7)
Cytoskeletal structural protein, cytoskeleton associated protein  Cytoskeletal structural protein, cytoskeleton associated protein
37582— at 0.003 6E-04 X07696 cytokeratin 15  37582—at 0.003 6E-04 X07696 cytokeratin 15
40776 at 0.109 0.363 M63391 desmin  40776 at 0.109 0.363 M63391 desmin
Extracellular matrix protein CO Extracellular matrix protein CO
39673 i at 0.026 0.039 AB011792 extracellular matrix protein 2 CO 39673 i at 0.026 0.039 AB011792 extracellular matrix protein 2 CO
Kinase and Phosphatase Kinase and Phosphatase
33787 at 0.003 6E-04 AB011 109 KIAA0537  33787 at 0.003 6E-04 AB011 109 KIAA0537
Enzyme (without protease, kinase, phosphatase and alcohol dehydrogenase)  Enzyme (without protease, kinase, phosphatase and alcohol dehydrogenase)
31704 at 0.327 0.562 U62647 deoxyribonuclease卜 like 2 (DNAS1L2)  31704 at 0.327 0.562 U62647 deoxyribonuclease like 2 (DNAS1L2)
33702 f at 0.086 0.157 L05144 phosphoenolpyruvate carboxykinase (PCK1 )  33702 f at 0.086 0.157 L05144 phosphoenolpyruvate carboxykinase (PCK1)
35345 at 0.003 0.031 X83618 3 - hydroxy— 3 - methylglutaryl coenzyme A synthase  35345 at 0.003 0.031 X83618 3-hydroxy-3- 3-methylglutaryl coenzyme A synthase
36512 at 0.016 0.392し 32179 arylacetamide deacetylase  36512 at 0.016 0.392 32179 arylacetamide deacetylase
36523 at 0.003 4E-04 L06133 ATPase, Cu++ transporting, alpha polypeptide ( ATP7A )  36523 at 0.003 4E-04 L06133 ATPase, Cu ++ transporting, alpha polypeptide (ATP7A)
38927 i at 0.016 0.579 M27160 tyrosinase (TYR)  38927 i at 0.016 0.579 M27160 tyrosinase (TYR)
41771一 g— at 0.006 0.034 AA420624 monoamine oxidase A  41 771 g-at 0.006 0.034 AA420624 monoamine oxidase A
41790 at 0.003 0.106 AL031230 Aldehyde dehydrogenase 5 family, member A1  41790 at 0.003 0.106 AL031230 Aldehyde dehydrogenase 5 family, member A1
Alcohol dehydroge nase  Alcohol dehydroge nase
34637 f at 0.003 0.02 M12963 alcohol dehydrogenase 1A (class I), alpha polypeptide  34637 f at 0.003 0.02 M12963 alcohol dehydrogenase 1A (class I), alpha polypeptide
36247 f at 0.018 M12272 alcohol dehydrogenase 1 C (class I), gamma polypeptide 36247 f at 0.018 M12272 alcohol dehydrogenase 1 C (class I), gamma polypeptide
Fatty acid metabo ism re ated molecule Fatty acid metabo ism re ated molecule
33337— at 0.004 0.001 AF002668 degenerative spermatocyte homolog ( sphingoiipid delta 4 desaturase )  33337—at 0.004 0.001 AF002668 degenerative spermatocyte homolog (sphingoiipid delta 4 desaturase)
35834 at 0.016 4E-04 X59766 alpha - 2— glycoprotein 1, zinc  35834 at 0.016 4E-04 X59766 alpha-2— glycoprotein 1, zinc
37122一 at 0.003 0.08 AB005293 perilipin  37122 one at 0.003 0.08 AB005293 perilipin
41209— at 0.01 0.151 M15856 lipoprotein lipase  41209—at 0.01 0.151 M15856 lipoprotein lipase
40409 at 0.003 0.004 U46689 aldehyde dehydrogenase 3 family, member A2  40409 at 0.003 0.004 U46689 aldehyde dehydrogenase 3 family, member A2
Grobin  Grobin
31525— s— at 0.003 0.017 JOOl 53 Hemoglobin alpha 1 , alpha 2 chain  31525— s— at 0.003 0.017 JOOl 53 Hemoglobin alpha 1, alpha 2 chain
Transcription factor and related molecule (Transcriptional regulator protein )  Transcription factor and related molecule (Transcriptional regulator protein)
37809 at 0.036 0.102 U41813 class I homeoprotein (HOXA9)  37809 at 0.036 0.102 U41813 class I homeoprotein (HOXA9)
39681 at 0.008 0.168 AF060568 promyelocytic leukemia zinc finger protein (PL2F)  39681 at 0.008 0.168 AF060568 promyelocytic leukemia zinc finger protein (PL2F)
CO  CO
Ion channe  Ion channe
37529 at 0.075 0.35 AF051946 calcium channel, voltage-dependent, alpha 1 H subunit  37529 at 0.075 0.35 AF051946 calcium channel, voltage-dependent, alpha 1 H subunit
39682 at 0.004 0.575 X87159 sodium channel, nonvoltage-gated 1 , beta  39682 at 0.004 0.575 X87159 sodium channel, nonvoltage-gated 1, beta
Others  Others
Membrane protein  Membrane protein
34800 at 0.004 0.002 AL039458 UG1 ( ortholog of mouse integral membrane glycoprotein UG- 1 〉  34800 at 0.004 0.002 AL039458 UG1 (ortholog of mouse integral membrane glycoprotein UG-1)
35164 at 0.028 0.119 AF084481 WFS1 ( Wolfram syndrome 1 )  35164 at 0.028 0.119 AF084481 WFS1 (Wolfram syndrome 1)
38821 at 0.003 5E-04 AJ002030 progesterone receptor membrane component 2  38821 at 0.003 5E-04 AJ002030 progesterone receptor membrane component 2
34412 s at 0.091 0.548 U59632 peanut-like 1 (Drosophila)  34412 s at 0.091 0.548 U59632 peanut-like 1 (Drosophila)
37983 at 0.006 0.023 S77410 type 1 angiotensin II receptor, variant 1—5  37983 at 0.006 0.023 S77410 type 1 angiotensin II receptor, variant 1-5
39930 at 0.01 0.006 D8349Z EphB6  39930 at 0.01 0.006 D8349Z EphB6
Secreted protein  Secreted protein
33975 at 0.18 0.363 S55606 betacel!ulin  33975 at 0.18 0.363 S55606 betacel! Ulin
36024 at 0.017 0.066 S79048 proline rich 4 (lacrimal)  36024 at 0.017 0.066 S79048 proline rich 4 (lacrimal)
Others  Others
32552 at 0.006 0.182 X00129 retinol binding protein 4  32552 at 0.006 0.182 X00129 retinol binding protein 4
33332一 at 0.18 Z93241 DKFZP434G0310 ( hypothetical protein )  33332 one at 0.18 Z93241 DKFZP434G0310 (hypothetical protein)
38851 at 0.003 0.008 M63394 loricrin 38851 at 0.003 0.008 M63394 loricrin
CO
Figure imgf000236_0001
CO
Figure imgf000236_0001
^^2 表 5 3 ^^ 2 Table 5 3
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間の比較で、 乾癬の皮疹部でのみ発現変動 （增加） した遺伝子を示した。 表中に記載されて いる、 †† † ΐは変動が 50倍以上、 † † ΐは 10〜50倍、 ††は 3〜： 10倍、 † は 2〜3倍、 一は変動なしであることを示す。 A comparison between atopic dermatitis (no rash and rash) and psoriasis (no rash and no rash) showed genes whose expression was altered (変 動) only in the rash of psoriasis. As shown in the table, 変 動 † 変 動 fluctuates 50 times or more, † † 10 10 to 50 times, †† 3 to 10 times, † 2 to 3 times, one is no change It indicates that.
50倍以上 1/50倍以下 50 times or more 1/50 times or less
ΤΤί 10-50倍 J* Ί- 1/50〜1/10倍  ΤΤί 10-50 times J * Ί- 1 / 50〜1 / 10 times
ίί 3-10倍 1/10~1/3倍  ίί 3-10 times 1/10 ~ 1/3 times
2-3倍 1/3~1/2倍  2-3 times 1/3 ~ 1/2 times
変動なし  No change
表 R-1：アトピー性皮膚炎と乾癬患者の皮膚組織における遺伝子発現を比較した結果、乾癬患者の皮膚組織でのみ Table R-1: Comparison of gene expression in skin tissues of patients with atopic dermatitis and psoriasis, only in skin tissues of patients with psoriasis
発現変動が認められた遺伝子  Genes with altered expression
(無疹部に比べて皮疹 I部で発現が増加していた遺伝子）  (Genes whose expression was increased in skin rash I compared to non-rash)
Probe ID Atopic Dermatitis Psoriasis  Probe ID Atopic Dermatitis Psoriasis
case case  case case
Probe ID 2 3 4 6 , 9 10 12 13 15 16 17 Ρ値 1 2 3 4 5 6 Ρ値 accession  Probe ID 2 3 4 6, 9 10 12 13 15 16 17 Low value 1 2 3 4 5 6 Low value accession
1057 at † ί - 一 一 - ' - τ τ - 一 2Ε-04 Τί τ Τί ίί ίί t ぐ 0001 Μ97815 1057 at † ί 一-one-'--τ τ-one 2Ε-04 Τί τ Τί ίί ίί t 0001 Μ 97815
1 184 at 一 ΐ ί 一 ' 一 - - ί 一 ίΤ - 0.052 ί 一 t 一 τ 0.003 D452481 184 at ΐ ΐ ί '' 1--ί ίΤ ίΤ-0.052 ί t t t τ 0.003 D45248
1358 s at ― ― 一 ― 一 - TT TT 一 †TT - 0.013 ΤίΤ ― TT ΤίΤ Τ1 ΤίΤ 0.01 U22970 t 1358 s at--one-one-TT TT one † TT-0.013 ΤίΤ-TT ΤίΤ Τ1 ΤίΤ 0.01 U22970 t
CO  CO
1480 at I † 6Ε-04 ί ί τ τ 0001 L12723 1480 at I † 6Ε-04 ί ί τ τ 0001 L12723
1516_g_at TT ίί ττ 0.003 τ τ ίΐ ίί ί 0.002 1516_g_at TT τ ττ 0.003 τ τ ίΐ ί ί 0.002
1521 at τ T ί ττ 0.013 ί τ ττ τ < 001 Χ17620 1521 at τ T ί ττ 0.013 ί τ ττ τ <001 Χ17620
1599 at it ΐί τ 0.013 ί τ Τΐ ίί 0.048 L258761599 at it τ τ 0.013 ί τ Τΐ ίί 0.048 L25876
1651 at † ίί η Τίί ぐ 0001 ί ίί ί ίί ί 0.067 U733791651 at † η η ぐ 0001 ί ίί ί ίί ί 0.067 U73379
1752 at ΐΐ 0.008 ττ ττ Τΐ Τί 0.028 AD0000921752 at ΐΐ 0.008 ττ ττ Τΐ Τί 0.028 AD000092
1803 at Τΐ Τΐ 0.027 ττ r ττ ί ττ ττ 0.005 Χ05360 1803 at Τΐ Τΐ 0.027 ττ r ττ ί ττ ττ 0.005 Χ05360
1839 at ί ί ί ί 2Ε-04 ί ί ΐ τ 〈·0001  1839 at ί ί ί ί 2Ε-04 ί ί τ τ 〈0001
1840一 g— at τ ί ί 4Ε-04 τ τ τ τ く.0001  1840-1 g—at τ ί ί 4Ε-04 τ τ τ τ
1962 at τ ϊ 0.815 ττ τ ί ττ ττ ΐ 0.003 Μ 14502  1962 at τ ϊ 0.815 ττ τ ί ττ ττ ΐ 0.003 Μ 14502
2018 at †† u πτ 0.205 ίίί Τί ίίί ίί ίίί 0.006 Μ65188 2018 at †† u πτ 0.205 ίίί Τί ίίί ίί ίίί 0.006 Μ65188
31343 at τ 0.014 Τί ίΤ ί ίΐ ίί 0.005 AJ00583531343 at τ 0.014 Τί ίΤ ί ίΐ ίί 0.005 AJ005835
31754 at ϊ 0.116 τ ττ τ ττ τ ίί 1 Ε-04 AL08020731754 at ϊ 0.116 τ ττ τ ττ τ ίί 1 Ε-04 AL080207
31864 at τ ΐ 7Ε-04 ΐ ΐ ί ττ τ 4Ε-04 Χ9826331864 at τ ΐ 7Ε-04 ΐ ΐ τττ τ 4Ε-04 Χ98263
31887 at τ ί 0.003 ί τ ί ίί Τί τ 0001 J0446931887 at τ ί 0.003 ί τ ί ίί τ τ 0001 J04469
32069 at τ τ † τ 9Ε-04 ί τ ί τ 4Ε-04 AB01451532069 at τ τ τ τ 9Ε-04 ί τ ί τ 4Ε-04 AB014515
32186 at ί ΐΤ 0.001 ί τ ί Τί τ ίί 7Ε-04 Μ8024432186 at ί ΐΤ 0.001 ί τ ί τ τ ίί 7Ε-04 Μ80244
32200 at U ί 0.623 t Τί ίί ί 0.006 24902 32200 at U ί 0.623 t Τί ίί ί 0.006 24902
32380 at 1 τ ΐ τ 0.001 ί ί ΐ Τί 3Ε-04 Ζ34974 32380 at 1 τ τ τ 0.001 ί ί ΐ Τί 3Ε-04 Ζ34974
Figure imgf000239_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000240_0001
Figure imgf000241_0002
Figure imgf000241_0002
Figure imgf000241_0001
Figure imgf000241_0001
2 4 1に ―—— Δ 2 4 1 ----
表 5 7  Table 5 7
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間の比較で、 乾癬の皮疹部でのみ発現変動 （増加） した遺伝子 （表 5 3〜表 5 6 ) の説明を 示した。 In comparison between atopic dermatitis (no rash and rash) and psoriasis (no rash and no rash), the expression of only the genes whose expression was changed (increased) only in the rash of psoriasis (Table 53 to Table 56) The explanation was given.
表 R- 1 (D):アトピー性皮膚炎と乾癬患者の皮膚組織における遺伝子発現を比較した結果、乾癬患者の皮膚組織でのみ Table R-1 (D): Comparison of gene expression in skin tissues of atopic dermatitis and psoriatic patients, only in skin tissues of psoriatic patients
発現変動が認められた違 ito子  Ito children with altered expression
AD PS  AD PS
Probe ID P値 P値 Accession Descriptions  Probe ID P value P value Accession Descriptions
1057 at 2E-04く.0001 97815 cellular retinoic acid binding protein 2  1057 at 2E-04.0001 97815 cellular retinoic acid binding protein 2
1 184 at 0.052 0.003 D45248 proteasome (prosome, macropain) activator subunit 2  1 184 at 0.052 0.003 D45248 proteasome (prosome, macropain) activator subunit 2
1358 s at 0.013 0.01 U22970 interferon induced 6— 16 protein  1358 s at 0.013 0.01 U22970 interferon induced 6— 16 protein
1480 at 6E-04く扁 1 L12723 heat shock 70kDa protein 4  1480 at 6E-04 Kuban 1 L12723 heat shock 70kDa protein 4
1516_g_at 0.003 0.002 flap structure-specific endonuclease 1  1516_g_at 0.003 0.002 flap structure-specific endonuclease 1
1521 at 0.013 0001 X17620 N E1  1521 at 0.013 0001 X17620 N E1
1599 at 0.013 0.048 L25876 cyclin— dependent kinase inhibitor 3  1599 at 0.013 0.048 L25876 cyclin— dependent kinase inhibitor 3
1651 at 〈扁 1 0.067 U73379 ubiquitin— conjugating enzyme E2C  1651 at <Ban 1 0.067 U73379 ubiquitin— conjugating enzyme E2C
1752 at 0.008 0.028 AD000092 calreticulin  1752 at 0.008 0.028 AD000092 calreticulin
1803 at 0.027 0.005 X05360 CDC2 gene  1803 at 0.027 0.005 X05360 CDC2 gene
1839 at 2E-04く扁 1 RAN  1839 at 2E-04 Kuben 1 RAN
1840一 g一 at 4E-04 (0001 RAN  1840 one g one at 4E-04 (0001 RAN
1962 at 0.815 0.003 M 14502 liver arginase (ARG1) t 1962 at 0.815 0.003 M 14502 liver arginase (ARG1) t
2018 at 0.205 0.006 M65188 connexin 43 (GJA1 , Cx43) 2018 at 0.205 0.006 M65188 connexin 43 (GJA1, Cx43)
31343 at 0.014 0.005 AJ005835 interleukin 1 receptor antagonist  31343 at 0.014 0.005 AJ005835 interleukin 1 receptor antagonist
31754 at 0.1 16 1 E-04 AL080207 ATP - binding cassette, sub-family A (ABC1)， member 12  31754 at 0.1 16 1 E-04 AL080207 ATP-binding cassette, sub-family A (ABC1), member 12
31864 at 7E-04 4E-04 X98263 M - phase phosphoprotein 6  31864 at 7E-04 4E-04 X98263 M-phase phosphoprotein 6
31887 at 0.003 〈細 1 J04469 creatine kinase, mitochondrial 1  31887 at 0.003 <fine 1 J04469 creatine kinase, mitochondrial 1
32069 at 9E-04 4E-04 AB014515 Nedd4 binding protein 1  32069 at 9E-04 4E-04 AB014515 Nedd4 binding protein 1
32186 at 0.001 7E-04 M80244 solute carrier family 7， member 5  32186 at 0.001 7E-04 M80244 solute carrier family 7, member 5
32200 at 0.623 0.006 M24902 acid phosphatase, prostate  32200 at 0.623 0.006 M24902 acid phosphatase, prostate
32380 at 0.001 3E-04 Z34974 f  32380 at 0.001 3E-04 Z34974 f
plakophilin I  plakophilin I
32392 s at 0.43 0.014 M57951 UDP glycosyltransferase 1 family, polypeptide A4  32392 s at 0.43 0.014 M57951 UDP glycosyltransferase 1 family, polypeptide A4
32482 at 0.083 0.002 L42563 ATPase, H+/K+ transporting, nongastric, alpha polypeptide  32482 at 0.083 0.002 L42563 ATPase, H + / K + transporting, nongastric, alpha polypeptide
32529 at 0001 0.001 X69910 cytoskeleton - associated protein 4  32529 at 0001 0.001 X69910 cytoskeleton-associated protein 4
32632一 g— at 0.05 5E-04 J03060 g!ucosidaset beta; acid 32632 one g—at 0.05 5E-04 J03060 g! Ucosidase t beta; acid
32814 at 0.142 0.015 M24594 interferon-inducible 56 Kd protein  32814 at 0.142 0.015 M24594 interferon-inducible 56 Kd protein
32855 at 0.003 5E-04 L00352 low density lipoprotein receptor  32855 at 0.003 5E-04 L00352 low density lipoprotein receptor
32868 at 0.032 0.008 L10386 transglutaminase 3  32868 at 0.032 0.008 L10386 transglutaminase 3
33029 at 0.099ぐ 0001 AF038461 arachidonate 12— lipoxygenase, 12R type 33029 at 0.099ugu 0001 AF038461 arachidonate 12— lipoxygenase, 12R type
33055 at 0.084 0.007 AF029403 CYP7B1 33055 at 0.084 0.007 AF029403 CYP7B1
33253 at 0.003 9E-04 D50919 tripartite moth" - containing 14  33253 at 0.003 9E-04 D50919 tripartite moth "-containing 14
33285 i at 0.534 0.022 W26762 hypothetical protein FLJ21168  33285 i at 0.534 0.022 W26762 hypothetical protein FLJ21168
33802 at 0.049 8E-04 Z82244 heme oxygenase (decycling) 1  33802 at 0.049 8E-04 Z82244 heme oxygenase (decycling) 1
34319 at 0.417 0.017 AA131149 S100 calcium binding protein P  34319 at 0.417 0.017 AA131149 S100 calcium binding protein P
34492 at 0.307 0.002 AL035297 gene from PAC 747L4  34492 at 0.307 0.002 AL035297 gene from PAC 747L4
34714— at 0.13 0.019 AL050267 SAM domain and HD domain 1  34714—at 0.13 0.019 AL050267 SAM domain and HD domain 1
35056 at 0.16 0.005 X97868 arylsulfatase F  35056 at 0.16 0.005 X97868 arylsulfatase F
35472一 at 0.208 0.059 Y10745 potassium inwardly - recthymg channel, subfamily J, member 15  35472 ichi at 0.208 0.059 Y10745 potassium inwardly-recthymg channel, subfamily J, member 15
35699 at 0.241 0.008 AF053306 BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)  35699 at 0.241 0.008 AF053306 BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)
35718 at 0.122 0.003 L22342 SP110 nuclear body protein isoform b  35718 at 0.122 0.003 L22342 SP110 nuclear body protein isoform b
35735 at 0.274 0.03 M55542' guanylate binding protein 1 (GBP1)  35735 at 0.274 0.03 M55542 'guanylate binding protein 1 (GBP1)
35820 at 0.006 2E-04 X62078 G 2 ganglioside activator protein  35820 at 0.006 2E-04 X62078 G 2 ganglioside activator protein
35822 at 0.1 0.002 L15702 complement factor B preproprotein  35822 at 0.1 0.002 L15702 complement factor B preproprotein
35839_at 0.017 0.001 D78130 squalene t  35839_at 0.017 0.001 D78130 squalene t
印 oxidase  Mark oxidase
35906 at 0.005 〈細 1 L29339 solute carrier family 5 (sodium/glucose cotransporter), member 1  35906 at 0.005 <fine 1 L29339 solute carrier family 5 (sodium / glucose cotransporter), member 1
35995— at 0.006 0.001 AF067656 2W10 interactor Zwint GO 35995—at 0.006 0.001 AF067656 2W10 interactor Zwint GO
36406 at 0.009 ぐ 0001 AA401397 kallikrein 13 36406 at 0.009 tick 0001 AA401397 kallikrein 13
36412 s at 0.003 0.007 U53831 interferon regulatory factor /  36412 s at 0.003 0.007 U53831 interferon regulatory factor /
36472 at 0.007 0.003 U32849 N-myc (and STAT) interactor  36472 at 0.007 0.003 U32849 N-myc (and STAT) interactor
36770 at 0.201 0.027 U18671 Stat2  36770 at 0.201 0.027 U18671 Stat2
36825 at 0.12 0.016 X82200 tripartite motiト containing 22  36825 at 0.12 0.016 X82200 tripartite motito containing 22
36837 at 0.085 0.053 U63743 kinesin-like 6  36837 at 0.085 0.053 U63743 kinesin-like 6
36838 at 0.006 5E-04 AF055481 kallikrein 10  36838 at 0.006 5E-04 AF055481 kallikrein 10
36922 at 0.051 4E-04 X59618 ribonucleotide reductase M2 polypeptide  36922 at 0.051 4E-04 X59618 ribonucleotide reductase M2 polypeptide
36927 at 0.129 0.025 AB000115 chromosome 1 open reading frame 29  36927 at 0.129 0.025 AB000115 chromosome 1 open reading frame 29
37126 at 0.26 0.01 M62800 Sjogren syndrome antigen A1  37 126 at 0.26 0.01 M62800 Sjogren syndrome antigen A1
37263 at 0.004 5E-04 U55206 gamma - glutamyl hydrolase  37263 at 0.004 5E-04 U55206 gamma-glutamyl hydrolase
37360 at 0.155 0.031 U66711 lymphocyte antigen 6 complex, locus E  37360 at 0.155 0.031 U66711 lymphocyte antigen 6 complex, locus E
37603 at 0.005 く細 1 X52015 interleukin-1 receptor antagonist  37603 at 0.005 fine 1 X52015 interleukin-1 receptor antagonist
37641 at 0.079 0.011 D28915 interferon— induced protein 44  37641 at 0.079 0.011 D28915 interferon-- induced protein 44
37754 at 0.019 0.024 L13210 lectin, galactoside-binding, soluble, 3 binding protein  37754 at 0.019 0.024 L13210 lectin, galactoside-binding, soluble, 3 binding protein
38265 at 0.045 0.002 A 38172 retinoblastoma binding protein 6  38265 at 0.045 0.002 A 38172 retinoblastoma binding protein 6
38549 at 0.254 0.018 AF026941 vipirin 38549 at 0.254 0.018 AF026941 vipirin
38584 at 0.188 0.015 AF026939 interferon - induced protein with tetratricopeptide repeats 4 38584 at 0.188 0.015 AF026939 interferon-induced protein with tetratricopeptide repeats 4
38879 at 0.939 0001 D83664 S100 calcium binding protein A12 (calgranulin C)  38879 at 0.939 0001 D83664 S100 calcium binding protein A12 (calgranulin C)
39061 at 0.03 0.007 D28137 bone marrow stromal cell antigen 2  39061 at 0.03 0.007 D28137 bone marrow stromal cell antigen 2
39109 at 0.017 0.004 AB024704 chromosome 20 open reading frame 1  39109 at 0.017 0.004 AB024704 chromosome 20 open reading frame 1
39249 at 6E-04 0.003 AB001325 aquaporin 3  39249 at 6E-04 0.003 AB001325 aquaporin 3
39581 at 0.024 4E-04 AA570193 cystatin A (stefin A)  39581 at 0.024 4E-04 AA570193 cystatin A (stefin A)
39677 at 0.068 0.013 D80008 KIAA0186  39677 at 0.068 0.013 D80008 KIAA0186
|r~  | r ~
40041 at 0.024 0.006 AF017790 retinoblastoma - assocほ ted protein HEC  40041 at 0.024 0.006 AF017790 retinoblastoma-assoc ted protein HEC
40122 at 6E-04ぐ 0001 AF037448 NS1 -associated protein 1  40122 at 6E-04 0001 AF037448 NS1 -associated protein 1
40145 at 0.005 0.006 AI375913 topoisomerase (DNA) II alpha 170kDa  40145 at 0.005 0.006 AI375913 topoisomerase (DNA) II alpha 170kDa
40195 at 0.106 0.057 XI 850 H2A histone family, member X  40195 at 0.106 0.057 XI 850 H2A histone family, member X
40385_at 0.001 0.017 U64197 chemokine exodus- 1  40385_at 0.001 0.017 U64197 chemokine exodus- 1
40412 at 0.003 0.003 AA2034/6 pituitary tumor-transforming 1  40412 at 0.003 0.003 AA2034 / 6 pituitary tumor-transforming 1
40639 at 0.037 0.005 AL021683 SCO cytochrome oxidase deficient homolog 2 (yeasU  40639 at 0.037 0.005 AL021683 SCO cytochrome oxidase deficient homolog 2 (yeasU
40690 at 0.001 4E-04 X54942 CDC28 protein kinase regulatory subunit 2 '  40690 at 0.001 4E-04 X54942 CDC28 protein kinase regulatory subunit 2 '
40726 at 0.107 0.001 U37426 kinesin-like 1  40726 at 0.107 0.001 U37426 kinesin-like 1
40735 at 0.513 0.005 D16626 histidine ammonia- lyase  40735 at 0.513 0.005 D16626 histidine ammonia-lyase
40982 at 3E-04 0.02 AA926957 hypothetical protein Fし J 10534
Figure imgf000245_0001
40982 at 3E-04 0.02 AA926957 hypothetical protein F and J 10534
Figure imgf000245_0001
41060 at 0.116 0.001 M74093 cyclin E1 41060 at 0.116 0.001 M74093 cyclin E1
41583 at 0.009 0.003 AC004770 flap structure-specific endonuclease 1  41583 at 0.009 0.003 AC004770 flap structure-specific endonuclease 1
41680 at 0.002 4E-04 AF007170 chromosome 1 open reading frame 34  41680 at 0.002 4E-04 AF007170 chromosome 1 open reading frame 34
41783 at 2E-04 3E-04 M97815 cellular retinoic acid binding protein 2  41783 at 2E-04 3E-04 M97815 cellular retinoic acid binding protein 2
572 at 0.219 0.015 M86699 TTK protein kinase  572 at 0.219 0.015 M86699 TTK protein kinase
617 at 0.662 0.003 M24902 acid phosphatase, prostate  617 at 0.662 0.003 M24902 acid phosphatase, prostate
664 at 0.077 0.044 L19593 interleukin 8 receptor beta L8RBJ  664 at 0.077 0.044 L19593 interleukin 8 receptor beta L8RBJ
ou»_at U.UU3 U.UU Uo /Uy4 DOT A ou »_at U.UU3 U.UU Uo / Uy4 DOT A
b /y at u.uuy ivl Uo l o b / y at u.uuy ivl Uo l o
910 at 0.029 0.009 M15205 thymidine kinase 1  910 at 0.029 0.009 M15205 thymidine kinase 1
915 at 0.126 0.018 M24594 interferon-inducible 56 Kd protein  915 at 0.126 0.018 M24594 interferon-inducible 56 Kd protein
973 at 5E-04 5E-04 Y10032 serum/glucocorticoid regulated kinase  973 at 5E-04 5E-04 Y10032 serum / glucocorticoid regulated kinase
1379 at 0.006 0.01 M59371 E。hA2  1379 at 0.006 0.01 M59371 E. hA2
1948 f at 0.156 0.003 U31511 nitric oxide synthase 2A  1948 f at 0.156 0.003 U31511 nitric oxide synthase 2A
33452 at 0.177 0.002 M15518 plasminogen activator, tissue type  33452 at 0.177 0.002 M15518 plasminogen activator, tissue type
33646— g一 at 0.044 <.0001 X61094 GM2 ganglioside activator protein 33646—g at at 0.044 <.0001 X61094 GM2 ganglioside activator protein
36336_s_at 0.552 0.019 AC005390隱 0963 protein 36336_s_at 0.552 0.019 AC005390 hidden 0963 protein
36407 at 0.001 〈崖 1 AL050220 kallikrein 13  36407 at 0.001 <Cliff 1 AL050220 kallikrein 13
37415 at 0.455 0.001 AB018258 ATPase, Class V, type 10B
Figure imgf000246_0001
37415 at 0.455 0.001 AB018258 ATPase, Class V, type 10B
Figure imgf000246_0001
38384 at 0.076 0.073 X54199 GART  38384 at 0.076 0.073 X54199 GART
^ 2 表 6 1 ^ 2 Table 6 1
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間の比較で、 乾癬の皮疹部でのみ発現変動 （減少） した遺伝子を示した。 表中に記載されて いる、 I 1 I I ¾ 1/50倍以下、 丄丄丄は 1/50〜： L/10倍、 丄丄は 1/10〜： 1/3倍、 上は 1/3〜1/2倍、 一は変動なしであることを示す。 Comparison between atopic dermatitis (no rash and rash) and psoriasis (no rash and no rash) showed a gene whose expression was altered (decreased) only in the rash of psoriasis. I 1 II い る 1/50 times or less, 丄 丄 丄 is 1/50 or more: L / 10 times, 丄 丄 is 1/10 or more: 1/3 times, and 1/3 is above 1/2 times, one indicates no change.
Τΐίί 50倍以上 1/50倍以下 Τΐίί 50 times or more 1/50 times or less
ΤΤί 10-50倍 "L i 1/50〜1/10倍  ΤΤί 10-50 times "L i 1 / 50-1 / 10 times
ίί 3- 10倍 U 1/10〜1/3倍  ίί 3 to 10 times U 1/10 to 1/3 times
2-3倍 1/3〜 /2倍  2-3 times 1/3 ~ / 2 times
変動なし  No change
Figure imgf000248_0001
Figure imgf000248_0001
, 74.
Figure imgf000249_0001
, 74.
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000250_0001
\一 - 表 64 \ One-Table 64
アトピー性皮膚炎 （無疹部と皮疹部） と乾癬 （無疹部と皮疹部） 間の比較で、 乾癬の皮疹部でのみ発現変動 （減少） した遺伝子 （表 61〜表 63) の説明を 示した。 A comparison between atopic dermatitis (no rash and rash) and psoriasis (no rash and no rash) explains the genes (Tables 61 to 63) whose expression was altered (decreased) only in the psoriatic rash. Indicated.
表 R-2(D):アトピー性皮膚炎と乾癬患者の皮膚組織における遺伝子発現を比較した結果、乾癬患者の皮膚組織でのみ Table R-2 (D): Comparison of gene expression in the skin tissues of patients with atopic dermatitis and psoriasis, only in skin tissues of psoriasis patients
発現変動が認められた il  Il with altered expression
AD PS  AD PS
Probe ID P値 P値 Accession Descriptions  Probe ID P value P value Accession Descriptions
32755 at 0.098 0.002 X13839 actin, alpha 2, smooth muscle, aorta  32755 at 0.098 0.002 X13839 actin, alpha 2, smooth muscle, aorta
1 197 at 0.039 0.003 D00654 actin, gamma 2, smooth muscle, enteric  1 197 at 0.039 0.003 D00654 actin, gamma 2, smooth muscle, enteric
1229 at 0.092 0.022 U78556 cisplatin resistance associated  1229 at 0.092 0.022 U78556 cisplatin resistance associated
1597 at 9E-04 0.025 L13720 growth arrest-specific 6  1597 at 9E-04 0.025 L13720 growth arrest-specific 6
1736 at 0.003 0.002 暖 402 insulin-like growth factor binding protein 6 (IGFBP6)  1736 at 0.003 0.002 warm 402 insulin-like growth factor binding protein 6 (IGFBP6)
35303 at 0.291 0.01 U96876 insulin induced protein 1 (INSIG1)  35303 at 0.291 0.01 U96876 insulin induced protein 1 (INSIG1)
1761 at 0.058 5E-04 D37965 PDGF receptor beta— like tumor suppressor (PRLTS)  1761 at 0.058 5E-04 D37965 PDGF receptor beta- like tumor suppressor (PRLTS)
1879 at 0.251 0.046 M14949 R-ras  1879 at 0.251 0.046 M14949 R-ras
33303 at 0.103 0.003 N21470 sarcospan (Kras oncogene - associated gene)  33303 at 0.103 0.003 N21470 sarcospan (Kras oncogene-associated gene)
2057— g_at 0.002 0.003 34641 fibroblast growth factor (FGF) receptor- 1  2057— g_at 0.002 0.003 34641 fibroblast growth factor (FGF) receptor-1
31 1 s at 0J65 0.026 M15801 fibronectin ι isoform 1 preproprotein t  31 1 s at 0J65 0.026 M15801 fibronectin ι isoform 1 preproprotein t
C7I C7I
32107 at 0.035 0.002 AL050173 chromosome 21 open reading frame 25 32107 at 0.035 0.002 AL050173 chromosome 21 open reading frame 25
32161 at 0.041 0.012 W26406 seven in absentia homolog 1 (Drosophila)  32161 at 0.041 0.012 W26406 seven in absentia homolog 1 (Drosophila)
39372 at 0.294 0.03 W26480 fatty acid desaturase 1  39372 at 0.294 0.03 W26480 fatty acid desaturase 1
39373 at 0.342 0.0D9 AF035284 fatty acid desaturase 1  39373 at 0.342 0.0D9 AF035284 fatty acid desaturase 1
41719 i at 0.508 0.053 AF009767 fatty acid desaturase 1  41719 i at 0.508 0.053 AF009767 fatty acid desaturase 1
32190 at 0.175 0.019 AL0501 18 fatty acid desaturase 2  32190 at 0.175 0.019 AL0501 18 fatty acid desaturase 2
32215 i at 0.002 0.009 AB020685 Rho - related BTB domain containing 3  32215 i at 0.002 0.009 AB020685 Rho-related BTB domain containing 3
32239 at 0.02 0.055 U69263 matrilin 2  32239 at 0.02 0.055 U69263 matrilin 2
32527 at ぐ 0001 0.004 鐘 1790 adipose specific 2  32527 at gus 0001 0.004 bell 1790 adipose specific 2
32542一 at 1E-04 0.004 AF063002 LIM protein  32542 one at 1E-04 0.004 AF063002 LIM protein
36065 at 0.075 0.004 AF052389 UM domain binding 2 1 CUMl  36065 at 0.075 0.004 AF052389 UM domain binding 2 1 CUMl
32847 at 0.025 0001 U48959 myosin light chain kinase (MLGK)  32847 at 0.025 0001 U48959 myosin light chain kinase (MLGK)
39145 at 0.089 0.006 J02854 myosin, light polypeptide 9, regulatory  39145 at 0.089 0.006 J02854 myosin, light polypeptide 9, regulatory
36791_g.at 0.014く細 1 19267 tropomyosin 1 (alpha)  36791_g.at 0.014 Fine 1 19267 tropomyosin 1 (alpha)
36792 at 0.007 4E-04 Z24727 tropomyosin 1 (alpha)  36792 at 0.007 4E-04 Z24727 tropomyosin 1 (alpha)
33232 at 0.285 1 E-04 細 7574 cysteine-rich protein 1 (intestinal)  33232 at 0.285 1 E-04 Fine 7574 cysteine-rich protein 1 (intestinal)
35234 at 0.009 0.007 D50406 reversion— inducing-cysteine - rich protein with kazaf motifs  35234 at 0.009 0.007 D50406 reversion— inducing-cysteine-rich protein with kazaf motifs
33756 at 0.003 0.034 U39447 amine oxidase, copper containing 3 (vascular adhesion protein 1)  33756 at 0.003 0.034 U39447 amine oxidase, copper containing 3 (vascular adhesion protein 1)
39031 at 8E-04 0.086 AA152406 cytochrome c oxidase subunit Vila polypeptide 1 (muscle) 39031 at 8E-04 0.086 AA152406 cytochrome c oxidase subunit Vila polypeptide 1 (muscle)
Figure imgf000253_0001
Figure imgf000253_0001
40339 at 0.021 0.034 U95367 GABA-A receptor pi subunit 40339 at 0.021 0.034 U95367 GABA-A receptor pi subunit
40398 s at 0.003 0.002 AI743406 mesenchyme homeo box 2 (growth arrest-specific homeo box;  40398 s at 0.003 0.002 AI743406 mesenchyme homeo box 2 (growth arrest-specific homeo box;
41294 at 0.013 0.003 AJ238246 keratin 7  41294 at 0.013 0.003 AJ238246 keratin 7
575 s at 0.024 0.005 M93036 tumor-associated calcium signal transducer 1  575 s at 0.024 0.005 M93036 tumor-associated calcium signal transducer 1
859 at 0.706 0.583 U03688 dioxin-inducible cytochrome P450 (CYPlBl)  859 at 0.706 0.583 U03688 dioxin-inducible cytochrome P450 (CYPlBl)
998 s at 0.148 0.167 X59770 interieukin 1 receptor, type II  998 s at 0.148 0.167 X59770 interieukin 1 receptor, type II
268 at 0.404 6E-04 L34657 platelet/endothelial cell adhesion molecule (CD31 antigen)  268 at 0.404 6E-04 L34657 platelet / endothelial cell adhesion molecule (CD31 antigen)
35253 at 0.026 0.077 ABO" 143 GRB2- associated binding protein 2  35253 at 0.026 0.077 ABO "143 GRB2-associated binding protein 2
36577— at 0.134 0.017 Z24725 ' mitogen inducible 2  36577—at 0.134 0.017 Z24725 '' mitogen inducible 2
36931一 at 0.296 0.005 95787 . transgelin  36931 one at 0.296 0.005 95787 .transgelin
37951 at 0.008 0.004 AF035119 deleted in liver cancer 1  37951 at 0.008 0.004 AF035119 deleted in liver cancer 1
CJ1 CJ1
38335 at 3E-04 0.003 U88620 8-oxoguanine DNA glycosylase 38335 at 3E-04 0.003 U88620 8-oxoguanine DNA glycosylase
CO  CO
40193 at 0.001 0.007 X51956 enolase 1、 (gamma, neuronal)  40193 at 0.001 0.007 X51956 enolase 1, (gamma, neuronal)
41574 at 0.171 3E-04 Y09703 pinin, desmosome associated protein  41574 at 0.171 3E-04 Y09703 pinin, desmosome associated protein
33442 at 0.153 5E-04 AB002365 KIAA0367 gene  33442 at 0.153 5E-04 AB002365 KIAA0367 gene
36612 at 0.144 0.08 D87470 IAA0280 gene  36612 at 0.144 0.08 D87470 IAA0280 gene
4Uooo at r n t; U.U l I AbU o9/D KlAAlUo protein  4Uooo at r n t; U.U l I AbU o9 / D KlAAlUo protein
41219 at 0.001 2E-04 AL050376瞧 0729 protein  41219 at 0.001 2E-04 AL050376 瞧 0729 protein
41826 at 0.06 0.01 W28287 K1AA1467 protein  41826 at 0.06 0.01 W28287 K1AA1467 protein
41620 at 0.8 7E-04 AB018259 KIAA0716 protein  41620 at 0.8 7E-04 AB018259 KIAA0716 protein
1527 s at 0.003 8E-04 U50527 hypothetical gene CG018  1527 s at 0.003 8E-04 U50527 hypothetical gene CG018
33878 at 0.034 0.013 W27472 hypothetical protein FLJ13612  33878 at 0.034 0.013 W27472 hypothetical protein FLJ13612
34303一 at 0.147 0.02 AL049949 FLJ90798  34303 one at 0.147 0.02 AL049949 FLJ90798
36092 at 0.017 0.003 AL080213 DKFZp586I1823  36092 at 0.017 0.003 AL080213 DKFZp586I1823
38312 at 0.008 2E-04 ALO50002 DKFZp5640222  38312 at 0.008 2E-04 ALO50002 DKFZp5640222
^66 2 5 4 \「ー―— 一—— ¾ ^ 66 2 5 4 \ "--------
健常人の正常組織とァトピー性皮膚炎患者および乾癬患者の無疹部間で発現変 動する遺伝子群の比較 Comparison of genes that fluctuate between normal tissues of healthy subjects and eruptions of patients with atopic dermatitis and psoriasis
6例の乾癬患者の無疹部における遺伝子発現と健常人 7例の正常組織における 遺伝子発現の比較に DNAチップ解析ソフトである GeneSpring4. 2 (Silicon Gene tics社） を用いた。 GeneSpring User Manualに従い、 Af f ymetrix社解析ソフト Suite4. 0による Absolute Analysisの結果を GeneSpringに取り込み、 同一チッ プ上の全ての遺伝子について各遺伝子の Average Difference値をその median 値で割り、 チップ内補正値 （補正値 A) を得た。 さらに各遺伝子について、 使用 した全てのチップにおける補正値 Aをその median値で割ることにより補正値 B を得た。 補正値 Bを用いてマン ·ホイットニ検定 (Mann-Whitney' s U test) を 行い、 患者無疹部と健常皮膚間で発現量に有意差のある遺伝子を選択した。 選 択した遺伝子群について、 更に、 患者無疹部と健常皮膚における各遺伝子の発 現量の平均値を比較して 2倍以上差のある遺伝子を選択した。  GeneSpring4.2 (Silicon Genetics), a DNA chip analysis software, was used to compare gene expression in the rash-free area of six psoriatic patients and gene expression in normal tissues of seven healthy subjects. In accordance with the GeneSpring User Manual, the results of Absolute Analysis by Affymetrix analysis software Suite 4.0 are imported into GeneSpring, and for all genes on the same chip, the Average Difference value of each gene is divided by its median value, and the correction value in the chip (Correction value A) was obtained. Further, for each gene, a correction value B was obtained by dividing the correction value A for all the chips used by the median value. Using the corrected value B, a Mann-Whitney's U test was performed, and genes having a significant difference in the expression level between the rash and the healthy skin were selected. From the selected gene groups, the average of the expression levels of each gene in the non-rash area of the patient and the healthy skin was compared, and genes having a difference of at least two times were selected.
患者無疹部に比較して健常皮膚で発現の高い遺伝子については健常人 7例の うち 4例以上で P (present)となる遺伝子のみを選択し、 患者無疹部で発現の 高い遺伝子については患者 6例のうち 4例以上で P となる遺伝子のみを選択し た。 選択した遺伝子群と実施例 3 で行った健常人正常組織とアトピー性皮膚炎 患者無疹部間の比較で発現変動が認められた遺伝子群を比較することにより、 ァトピー性皮膚炎と乾癬で共通変動する遺伝子、 ァトピー性皮膚炎でのみ発現 変動を示す遺伝子、 乾癬でのみ発現変動を示す遺伝子を同定した。  Only genes that are P (present) in at least 4 out of 7 healthy subjects were selected for genes that are expressed in healthy skin compared to the non-rash area of patients. Only genes with P in at least 4 out of 6 patients were selected. By comparing the selected gene group with the normal tissues of healthy subjects and the atopic dermatitis patients in Example 3 where the gene group whose expression was fluctuated was compared, it was common for atopic dermatitis and psoriasis. Genes that fluctuate, genes whose expression changes only in atopic dermatitis, and genes whose expression changes only in psoriasis were identified.
アトピー性皮膚炎と乾癬で共通変動した遺伝子群を表 6 7〜表 6 9に、 アト ピー性皮膚炎でのみ発現変動を示した遺伝子群を表 7 0〜表 7 2に、 乾癬での み発現変動を示した遺伝子群を表 7 3〜表 7 5に示した。 各疾患特異的に発現 変動するとして同定した遺伝子については、 他方の疾患における発現プロファ ィルも表中に併記した。 各疾患特異的変動遺伝子として同定した遺伝子の中に は、 他方の疾患においても統計的に有意な変動を示しているように見える遺伝 子が認められるが、 これらの遺伝子は全て我々の選択基準を満たさないもので あった （2倍以下の変動倍率で有意差が認められたか、 あるいは GeneChip の検 出限界以下の定量値を用いた統計解析で有意差力 S認められた遺伝子)。 Tables 67 to 69 list the genes that fluctuated commonly in atopic dermatitis and psoriasis, and Tables 70 to 72 show the genes that fluctuated only in atopic dermatitis. Tables 73 to 75 show the gene groups showing the expression fluctuation. For genes identified as having expression fluctuations specific to each disease, the expression profile for the other disease is also shown in the table. Among the genes identified as disease-specific variation genes, some genes that appear to show statistically significant variation in the other disease However, all of these genes did not meet our selection criteria (a significant difference was observed at a fold change of 2 times or less, or a quantitative value below the detection limit of the GeneChip was used). Genes with significant difference S in statistical analysis).
表 6 7  Table 6 7
ァトピー性皮膚炎患者の無疹部または乾癬患者の無疹部と健常人の正常組織 間の比較で、 両疾患で共通変動 （増加） した遺伝子を示した。 Comparison between the eruptions of atopic dermatitis patients or the eruptions of psoriatic patients and normal tissues of healthy subjects showed genes that were commonly altered (increased) in both diseases.
表 P-1：アトピー性皮膚炎と乾癬患者の皮膚組織における遺伝子発現を比較した結果、両疾患患者の皮膚組織で共通して発現変動 が認められた遺伝子 (健常人の正常組織に比べてアトピー性皮膚炎および乾癬患者無疹部で発現が増加していた遺伝子) Table P-1: Comparison of gene expression in skin tissues of patients with atopic dermatitis and psoriasis showed that genes whose expression was changed in common in skin tissues of patients with both diseases (topy compared to normal tissues of healthy subjects) (Expression increased in the eruption of patients with atopic dermatitis and psoriasis)
Figure imgf000257_0001
Figure imgf000257_0001
T JP2003/009808 T JP2003 / 009808
2 5 」 twenty five "
表 6 8  Table 6 8
ァトピー性皮膚炎患者の無疹部または乾癬患者の無疹部と健常人の正常組織 間の比較で、 両疾患で共通変動 （減少） した遺伝子を示した。 A comparison between the eruptions of atopic dermatitis patients or the eruptions of psoriatic patients and normal tissues of healthy subjects showed genes that were commonly altered (decreased) in both diseases.
Figure imgf000259_0001
Figure imgf000259_0001
547 s at 11.475 1.026 1 E-04 2.236 0.177 5E-04 S77154 nuclear receptor subfamily 4, group A, member 2 547 s at 11.475 1.026 1 E-04 2.236 0.177 5E-04 S77154 nuclear receptor subfamily 4, group A, member 2
TR3 ( nuclear receptor subfamily 4, group A,  TR3 (nuclear receptor subfamily 4, group A,
279 at 5.235 0.964 0.003 2.28 0.505 0.039 L13740 member 1 )  279 at 5.235 0.964 0.003 2.28 0.505 0.039 L13740 member 1)
TR3 ( nuclear receptor subfamily 4, group A,  TR3 (nuclear receptor subfamily 4, group A,
280 g at 1 1.31 1.428 3E-04 2.652 0.568 0.008 L13740 member 1 )  280 g at 1 1.31 1.428 3E-04 2.652 0.568 0.008 L13740 member 1)
37623一 at 13.291 1.264 I E- 04 1.826 0.212 0.002 X75918 NOT  37623 one at 13.291 1.264 I E-04 1.826 0.212 0.002 X75918 NOT
36979 at 3.32 0.91 4E-05 1.902 0.755 0.008 M20681 glucose transporter-like protein-III (GLUT3) DO  36979 at 3.32 0.91 4E-05 1.902 0.755 0.008 M20681 glucose transporter-like protein-III (GLUT3) DO
GADD45B ( growth arrest and DNA-damageHnducible,  GADD45B (growth arrest and DNA-damageHnducible,
39822 s at 2.381 0.9 0.001 1.567 0.512 0.008 AF078077 beta )  39822 s at 2.381 0.9 0.001 1.567 0.512 0.008 AF078077 beta)
595 at 3.497 0.948 0.003 1.793 0.62 0.024 59465 tumor necrosis factor alpha inducible protein A20  595 at 3.497 0.948 0.003 1.793 0.62 0.024 59465 tumor necrosis factor alpha inducible protein A20
38772 at 4.383 0.796 4E-05 1.349 0.487 0.039 Y11307 CYR61  38772 at 4.383 0.796 4E-05 1.349 0.487 0.039 Y11307 CYR61
41048 at 1.81 0.679 0.002 1.534 0.7 0.039 D90070 APR ( ATL-derived P A-responsive gene )  41048 at 1.81 0.679 0.002 1.534 0.7 0.039 D90070 APR (ATL-derived P A-responsive gene)
39829— at 1.897 0.536 9E-05 1.392 0.636 0.004 AB016811 ADP- ribosylation factor-like 7  39829—at 1.897 0.536 9E-05 1.392 0.636 0.004 AB016811 ADP-ribosylation factor-like 7
41 102 at 1.432 0.681 0.023 2.54 0.519 0.013 U66359 T54 protein  41 102 at 1.432 0.681 0.023 2.54 0.519 0.013 U66359 T54 protein
31523 f at 1.742 0.837 0.023 1.659 0.593 0.024 Z80780 H2B histone family, member H  31523 f at 1.742 0.837 0.023 1.659 0.593 0.024 Z80780 H2B histone family, member H
36234 at 2.136 0.934 5E-04 1.619 0.665 0.002 U79273 clone 23933  36234 at 2.136 0.934 5E-04 1.619 0.665 0.002 U79273 clone 23933
35878 at 3.188 0.862 2E-05 1.739 0.774 0.024 AB023141 KIAA0924  35878 at 3.188 0.862 2E-05 1.739 0.774 0.024 AB023141 KIAA0924
^69 表 7 0 ^ 69 Table 70
ァトピー性皮膚炎患者の無疹部または乾癬患者の無疹部と健常人の正常組織 間の比較で、 アトピー性皮膚炎患者の無疹部でのみ発現変動 （増加） した遺伝 子を示した。 A comparison between the eruptions of atopic dermatitis patients or the eruptions of psoriatic patients and the normal tissues of healthy subjects showed genes whose expression was altered (increased) only in the eruptions of atopic dermatitis patients.
Figure imgf000262_0001
Figure imgf000262_0001
1 表 7 1 One Table 7 1
ァトピー性皮膚炎患者の無疹部または乾癬患者の無瘆部と健常人の正常組織 間の比較で、 アトピー性皮膚炎患者の無疹部でのみ発現変動 （減少） した遺伝 子を示した。 A comparison between the non-rash area of atopic dermatitis patients or the non-rash area of psoriasis patients and the normal tissues of healthy subjects showed genes whose expression was altered (decreased) only in the non-rash area of atopic dermatitis patients.
Figure imgf000264_0001
Figure imgf000264_0001
32565 at 1.858 0.731 0.037 1.294 1.232 1 U66619 SMARCD3 32565 at 1.858 0.731 0.037 1.294 1.232 1 U66619 SMARCD3
39014 at 2.364 0.929 0.01 1.191 1.1 12 0.499 D84239 IgG Fc binding protein  39014 at 2.364 0.929 0.01 1.191 1.1 12 0.499 D84239 IgG Fc binding protein
1 122 f at 2.395 0.952 5E-04 0.908 1.079 0.12 K03183 chorionic gonadotropin beta subunit  1 122 f at 2.395 0.952 5E-04 0.908 1.079 0.12 K03183 chorionic gonadotropin beta subunit
31594 at 2.289 0.889 0.049 2.145 1.051 0.59 Y16788 keratin, hair, acidic, 3A  31594 at 2.289 0.889 0.049 2.145 1.051 0.59 Y16788 keratin, hair, acidic, 3A
32057 at 1.921 0.718 0.007 1.429 1.097 0.415 U32907 37 kDa leucine-rich repeat (LRR) protein  32057 at 1.921 0.718 0.007 1.429 1.097 0.415 U32907 37 kDa leucine-rich repeat (LRR) protein
32606 at 1.662 0.823 0.013 0.971 0.964 0.789 AA135683 brain abundant membrane attached signal protein 1  32606 at 1.662 0.823 0.013 0.971 0.964 0.789 AA135683 brain abundant membrane attached signal protein 1
32607 at 2.107 0.845 8E-06 1.56 1.182 0.59 AF039656 brain abundant, membrane attached signal protein 1  32607 at 2.107 0.845 8E-06 1.56 1.182 0.59 AF039656 brain abundant, membrane attached signal protein 1
32770 at 2.198 0.804 0.007 1.378 1.201 0.499 AB018298 SEC24 related gene family, member D (S. cerevisiae)  32770 at 2.198 0.804 0.007 1.378 1.201 0.499 AB018298 SEC24 related gene family, member D (S. cerevisiae)
33202 f at 1.642 0.705 0.001 0.926 1.154 0.059 U43747 Friedreich ataxia  33202 f at 1.642 0.705 0.001 0.926 1.154 0.059 U43747 Friedreich ataxia
33220 at 2.124 0.884 0.005 1.037 1.102 0.59 Z11773 zinc finger protein 187  33220 at 2.124 0.884 0.005 1.037 1.102 0.59 Z11773 zinc finger protein 187
37860 at 2.209 0.99 : 0:002 0.988 1.091 0.789 AL049942 zinc finger protein 337  37860 at 2.209 0.99: 0: 002 0.988 1.091 0.789 AL049942 zinc finger protein 337
33773 at 1.804 0.864 0.01 0.966 1.01 0.789 U13948 LLT10  33773 at 1.804 0.864 0.01 0.966 1.01 0.789 U13948 LLT10
34388 at 3.516 0.836 0.002 2.23 1.193 0.894 Y1 1710 collagen, type XIV, alpha 1 (undulin)  34388 at 3.516 0.836 0.002 2.23 1.193 0.894 Y1 1710 collagen, type XIV, alpha 1 (undulin)
35399 at 1.796 0.896 0.03 0.861 0.94 0.59 AF102544 molybdenum cofactor synthesis 3 (35 guanylate binding protein 1， interferon- inducible,  35399 at 1.796 0.896 0.03 0.861 0.94 0.59 AF102544 molybdenum cofactor synthesis 3 (35 guanylate binding protein 1, interferon-inducible,
35735 at 2.176 0.826 9E-04 1.038 1.154 0.687 M55542 67kDa  35735 at 2.176 0.826 9E-04 1.038 1.154 0.687 M55542 67kDa
35803 at 1.933 0.877 0.002 1.466 0.91 1 0.212 S82240 ras homolog gene family, member E  35803 at 1.933 0.877 0.002 1.466 0.91 1 0.212 S82240 ras homolog gene family, member E
36057 at 1.637 0.739 0.007 0.994 0.864 0.499 AB01 1084 armadillo repeat protein ALEX2  36057 at 1.637 0.739 0.007 0.994 0.864 0.499 AB01 1084 armadillo repeat protein ALEX2
36310 at 4.065 1.034 0.007 3.088 1.121 0.59 X86570 keratin, hairr acidic, 1 36310 at 4.065 1.034 0.007 3.088 1.121 0.59 X86570 keratin, hair r acidic, 1
37079 at 2.164 0.781 0.001 1.051 1.026 0.789 U82319 YDD 19 protein  37079 at 2.164 0.781 0.001 1.051 1.026 0.789 U82319 YDD 19 protein
37927 at 1.66 0.701 0.023 0.949 0.879 0.789 X12654 chromosome condensation 1  37927 at 1.66 0.701 0.023 0.949 0.879 0.789 X12654 chromosome condensation 1
38058 at 1J64 0.795 2E-04 0.987 1.166 0.415 Z22865 dermatopontin  38058 at 1J64 0.795 2E-04 0.987 1.166 0.415 Z22865 dermatopontin
39710 at 2.074 0.99 0.01 1.298 0.927 0.789 画 21 P311 protein  39710 at 2.074 0.99 0.01 1.298 0.927 0.789 Image 21 P311 protein
39857 at 2.128 0.477 I E- 03 0.953 0.907 0.789 AF044309 syntaxin 11  39857 at 2.128 0.477 I E- 03 0.953 0.907 0.789 AF044309 syntaxin 11
40500 at 2.46 0.809 0.023 1.778 0.934 0.687 AF007138 NDRG family member 4  40500 at 2.46 0.809 0.023 1.778 0.934 0.687 AF007138 NDRG family member 4
41852 at 1.859 0.909 9E-05 1.154 0.884 0.12 U22377 rearranged L-myc fusion sequence  41852 at 1.859 0.909 9E-05 1.154 0.884 0.12 U22377 rearranged L-myc fusion sequence
41864 at 1.983 0.985 0.023 1.248 1.02 0.687 AF052181 clone 24790  41864 at 1.983 0.985 0.023 1.248 1.02 0.687 AF052181 clone 24790
33240 at 2.419 0.916 0.023 2.006 1.054 1 AB029018 KIAA1095 protein  33240 at 2.419 0.916 0.023 2.006 1.054 1 AB029018 KIAA1095 protein
34778 at 2.412 1.029 0.03 1.712 0.992 0.687 AA418080 FLJ 12280  34778 at 2.412 1.029 0.03 1.712 0.992 0.687 AA418080 FLJ 12280
35007 at 1.548 0.751 0.001 1.047 0.955 0.59 AC004940 ESTs  35007 at 1.548 0.751 0.001 1.047 0.955 0.59 AC004940 ESTs
34093 at 1.944 0.915 0.01 0.91 1.01 0.789 AI829701 ESTs  34093 at 1.944 0.915 0.01 0.91 1.01 0.789 AI829701 ESTs
2 表 7 3 Two Table 7 3
ァトピー性皮膚炎患者の無疹部または乾癬患者の無疹部と健常人の正常組織 間の比較で、 乾癬患者の無疹部でのみ発現変動 （増加） した遺伝子を示した。 A comparison between the eruptions of atopic dermatitis patients or the eruptions of psoriatic patients and the normal tissues of healthy subjects showed that genes whose expression was altered (increased) only in the eruptions of psoriatic patients.
表 S- 1 ·.アトピー性皮膚炎と乾癬患者の皮膚組織における遺伝子発現を比較した結果、乾癬患者の皮虜組織でのみ Table S-1 · Comparison of gene expression in skin tissues of patients with atopic dermatitis and psoriasis.
発現変動が認められた遺伝子 (健常人の正常組織に比べて乾癣患者無疹部で発現が増加していた遺伝子）  Genes whose expression was fluctuated (genes whose expression was increased in the eruptions of psoriasis patients compared to normal tissues of healthy subjects)
Increase (健常人 <乾癬無疹部）  Increase (Healthy person <Psoriasis-free part)
健常人 ·乾癣無疹部比較 健常人 ·Α0無疹部比較  Healthy person · dry area without rash Free healthy person · Α0 area without rash
発現量 (補正値 Bの平均値） 発現量 (補正値 Βの平 j匀値）  Expression level (average value of correction value B) Expression level (correction value 平 flat j 匀 value)
Probe 健常人 乾癬無疹^ P値 健常人 AD無疹部 P値 Accession Description  Probe Healthy person Psoriasis no eruption ^ P value Healthy person AD no rash part P value Accession Description
1 1 15 at 0.714 1.763 0.004 1.052 1.153 0.808 M25897 platelet factor 4 (PF4)  1 1 15 at 0.714 1.763 0.004 1.052 1.153 0.808 M25897 platelet factor 4 (PF4)
1 197 at 0.83 1.708 0.014 0.848 1.252 0.214 D00654 actin, gamma 2, smooth muscle, enteric  1 197 at 0.83 1.708 0.014 0.848 1.252 0.214 D00654 actin, gamma 2, smooth muscle, enteric
1589 s at 0.607 1.655 0.004 0.752 1.028 0.406 L42243 interferon (alpha, beta and omega) receptor 2  1589 s at 0.607 1.655 0.004 0.752 1.028 0.406 L42243 interferon (alpha, beta and omega) receptor 2
1710 s at 0.519 1.397 0.024 0.998 1.256 0.568 U07804 DMA topoisomerase I  1710 s at 0.519 1.397 0.024 0.998 1.256 0.568 U07804 DMA topoisomerase I
1756 f at 0.83 1.728 1 E-04 0.903 1.001 0.367 D00003 CYP3A4  1756 f at 0.83 1.728 1 E-04 0.903 1.001 0.367 D00003 CYP3A4
1833 at 0.578 1.546 0.024 1.207 1.597 0.623 M68520 cyclin-dependent kinase 2  1833 at 0.578 1.546 0.024 1.207 1.597 0.623 M68520 cyclin-dependent kinase 2
1958 at 0.43 1.716 0.022 2.272 2.463 0.797 AJ000185 vascular endothelial growth facto「D  1958 at 0.43 1.716 0.022 2.272 2.463 0.797 AJ000185 vascular endothelial growth facto `` D
2041 i at 0.549 1.325 0.024 0.633 1.625 0.109 M14752 ABL1 t 2041 i at 0.549 1.325 0.024 0.633 1.625 0.109 M14752 ABL1 t
32146 s at 0.448 1.28 0.019 0.488 1.463 0.045 L07261 adducin 1 (alpha) isoform c 32146 s at 0.448 1.28 0.019 0.488 1.463 0.045 L07261 adducin 1 (alpha) isoform c
32287 s at 0.628 2.071 0.004 0.813 1.471 0.182 AJ001685 Kし RG3  32287 s at 0.628 2.071 0.004 0.813 1.471 0.182 AJ001685 K then RG3
32581 at 0.509 1.352 0.007 0.509 1.156 0.036 AF070629 RAB2
Figure imgf000267_0001
32581 at 0.509 1.352 0.007 0.509 1.156 0.036 AF070629 RAB2
Figure imgf000267_0001
32837 at 0.97 2.333 0.024 0.925 1.336 0.061 U56418 1 -acylglyceroト 3— phosphate O-acyltransferase 2 32837 at 0.97 2.333 0.024 0.925 1.336 0.061 U56418 1 -acylglycero to 3-phosphate O-acyltransferase 2
32905 s at 0.808 1.627 5E-04 0.952 0.967 0.685 M30038 tryptase, alpha  32905 s at 0.808 1.627 5E-04 0.952 0.967 0.685 M30038 tryptase, alpha
32975_g.at 0.447 1.094 0.014 1.533 1.102 0.655 U07563 homolog of Yeast RRP4  32975_g.at 0.447 1.094 0.014 1.533 1.102 0.655 U07563 homolog of Yeast RRP4
33252 at 0.669 1.372 0.004 0.689 1.187 0.061 D38073 CM3  33252 at 0.669 1.372 0.004 0.689 1.187 0.061 D38073 CM3
33516 at 0.681 1.703 5E-04 0.874 1.144 0.248 ■505 hemoglobin, delta  33516 at 0.681 1.703 5E-04 0.874 1.144 0.248505 hemoglobin, delta
34868 at 0.549 1.472 0.014 0.7 1.362 0.023 AB0Z9012 KIAA1089  34868 at 0.549 1.472 0.014 0.7 1.362 0.023 AB0Z9012 KIAA1089
35409 r at 0.719 1.528 0.039 0.775 1.423 0.247 X16281 zinc finger protein 44 (KOX 7)  35409 r at 0.719 1.528 0.039 0.775 1.423 0.247 X16281 zinc finger protein 44 (KOX 7)
36512 at 0J73 1.564 0.014 0.839 1.343 0.091 L32179 arylacetamide deacetylase (esterase)  36512 at 0J73 1.564 0.014 0.839 1.343 0.091 L32179 arylacetamide deacetylase (esterase)
36555 at 0.544 2.752 0.024 1.784 1.671 0.968 AF04431 1 synuclein, gamma  36555 at 0.544 2.752 0.024 1.784 1.671 0.968 AF04431 1 synuclein, gamma
37096 at 1.426 8.813 0.036 3.337 15.315 0.22 34379 elastase 2, neutrophil  37096 at 1.426 8.813 0.036 3.337 15.315 0.22 34379 elastase 2, neutrophil
37124丄 at 0.89 1.875 0.039 0.89 1.081 0.1 1 J04813 CYP3A5  37124 丄 at 0.89 1.875 0.039 0.89 1.081 0.1 1 J04813 CYP3A5
37200 at 0.69 1.968 0.008 0.646 1.258 0.007 J04162 FCGR3A (CD16)  37200 at 0.69 1.968 0.008 0.646 1.258 0.007 J04162 FCGR3A (CD16)
37630 at 0.863 1.726 0.024 0.961 0.958 0.936 AL049176 likely ortholog of mouse neuralin 1  37630 at 0.863 1.726 0.024 0.961 0.958 0.936 AL049176 likely ortholog of mouse neuralin 1
38000 at 0.933 1.913 0.039 1.281 1.059 0.463 S72370 pyruvate carboxylase  38000 at 0.933 1.913 0.039 1.281 1.059 0.463 S72370 pyruvate carboxylase
38388 at 0.625 1.358 0.024 0.888 1.025 0.625 11810 2',5'-oligoadenylate synthetase 1  38388 at 0.625 1.358 0.024 0.888 1.025 0.625 11810 2 ', 5'-oligoadenylate synthetase 1
38540一 at 0.645 1.891 0.008 0.838 1.335 0.54 AF043938 muscle RAS oncogene homolog 38540 at 0.645 1.891 0.008 0.838 1.335 0.54 AF043938 muscle RAS oncogene homolog
38760 f at 0.783 1.57 0.002 1.061 1.041 0.936 U90546 butyrophilin, subfamily 3, member A2 38760 f at 0.783 1.57 0.002 1.061 1.041 0.936 U90546 butyrophilin, subfamily 3, member A2
39208 i at 0.489 3.121 5E-04 0.692 1.906 0.06 54995 connective tissue activation peptide III  39208 i at 0.489 3.121 5E-04 0.692 1.906 0.06 54995 connective tissue activation peptide III
39209 r at 0.793 3.141 0.002 0.893 1.082 0.871 M54995 connective tissue activation peptide III  39209 r at 0.793 3.141 0.002 0.893 1.082 0.871 M54995 connective tissue activation peptide III
39295 s at 0.725 1.813 0.008 0.791 1.074 0.248 AF049884 Arg/Abl-interacting protein ArgBP2  39295 s at 0.725 1.813 0.008 0.791 1.074 0.248 AF049884 Arg / Abl-interacting protein ArgBP2
39296 at 0.371 1.57 0.005 2.06 5.273 0.162 W28319 FLJ33034  39296 at 0.371 1.57 0.005 2.06 5.273 0.162 W28319 FLJ33034
39301 at 0.49 1.132 0.024 0.518 1.006 0.054 X85030 calpain 3  39301 at 0.49 1.132 0.024 0.518 1.006 0.054 X85030 calpain 3
394 at 0.875 2.087 0.002 0.875 1.387 0.075 X92106 bleomycin hydrolase tSD 394 at 0.875 2.087 0.002 0.875 1.387 0.075 X92106 bleomycin hydrolase tSD
39544 at 0.765 1.537 0.024 0.911 1.247 0.156 AB002351 desmuslin CD39544 at 0.765 1.537 0.024 0.911 1.247 0.156 AB002351 desmuslin CD
39908 at 0.752 2.045 IE- 04 0.867 1.343 0.038 AF069735 TAF6L —39908 at 0.752 2.045 IE-04 0.867 1.343 0.038 AF069735 TAF6L —
40428 i at 0.653 1.569 0.024 0.778 2.06 0.156 AW043812 ESTs 40428 i at 0.653 1.569 0.024 0.778 2.06 0.156 AW043812 ESTs
40772 at 0.819 1.725 0.039 0.959 1.1 0.746 AA284298 FLJ22269  40772 at 0.819 1.725 0.039 0.959 1.1 0.746 AA284298 FLJ22269
41294 at 0.814 1.796 0.002 0.848 1.141 0.1 1 AJ238246 keratin 7  41294 at 0.814 1.796 0.002 0.848 1.141 0.1 1 AJ238246 keratin 7
41315 at 0.39 1.539 1 E-04 2.124 1.785 0.935 AA456343 scaffold attachment factor B  41315 at 0.39 1.539 1 E-04 2.124 1.785 0.935 AA456343 scaffold attachment factor B
41387 r at 0.483 1.058 0.024 2.008 1.325 0.508 AB002344隱 0346  41387 r at 0.483 1.058 0.024 2.008 1.325 0.508 AB002344 Hidden 0346
425 at 0.505 1.663 0.024 0.822 1.607 0.038 X67325 interferon, alpha-inducible protein 27  425 at 0.505 1.663 0.024 0.822 1.607 0.038 X67325 interferon, alpha-inducible protein 27
459 s at 0.461 1.462 0.014 1.576 1.463 0.903 U68485 bridging integrator 1  459 s at 0.461 1.462 0.014 1.576 1.463 0.903 U68485 bridging integrator 1
773 at 0.565 1.749 0.004 1.077 1.405 0.936 D10667 smooth muscle myosin heavy chain  773 at 0.565 1.749 0.004 1.077 1.405 0.936 D10667 smooth muscle myosin heavy chain
774 at 0.88 1.955 0.039 1.167 1.25 0.515 D10667 smooth muscle myosin heavy chain  774 at 0.88 1.955 0.039 1.167 1.25 0.515 D10667 smooth muscle myosin heavy chain
4 表 7 5 Four Table 7 5
ァトピー性皮膚炎患者の無疹部または乾癬患者の無疹部と健常人の正常組織 間の比較で、 乾癬患者の無疹部でのみ発現変動 （減少） した遺伝子を示した。 A comparison between the eruptions of atopic dermatitis patients or the eruptions of psoriatic patients and the normal tissues of healthy subjects showed genes whose expression was altered (decreased) only in the eruptions of psoriatic patients.
表 S- 2 :アトピー性皮膚炎と乾癬患者の皮膚組織における遺伝子発現を比較した結果、乾癬患者の皮膚組織でのみ Table S-2: Comparison of gene expression in skin tissues of patients with atopic dermatitis and psoriasis.
発現変動が認められた遺伝子 (健常人の正常組織に比べて乾癬患者無瘆部で発現が低下していた遺伝子)  Genes with fluctuated expression (genes whose expression was lower in the normal part of psoriatic patients than normal tissues of healthy subjects)
Decrease (健常人 >乾癬無疹部） ' Decrease (healthy> psoriasis-free part) ''
健常人 ·乾癬無疹部比較 健常人，AD無疹部比較  Healthy person · Psoriasis-free area comparison Healthy person – AD-free area comparison
発現量 (補正値 Bの平均値） 発現量 (補正値 Bの平均値）  Expression level (average value of correction value B) Expression level (average value of correction value B)
Probe CD 健常人 乾癬無疹剖 P値 健常人 AD無疹部 P値 Accession Description  Probe CD Normal psoriasis-free autopsy P-value Healthy human AD no-rash P-value Accession Description
CD  CD
31522 f at 1.56 0.67 0.039 1.401 0.957 0.075 Z80779 H2B histone Tamily, member G  31522 f at 1.56 0.67 0.039 1.401 0.957 0.075 Z80779 H2B histone Tamily, member G
33568 at 1.767 0.776 0.039 1.521 0.92 0.214 U48861 cholinergic receptor, nicotinic, beta polypeptide 4  33568 at 1.767 0.776 0.039 1.521 0.92 0.214 U48861 cholinergic receptor, nicotinic, beta polypeptide 4
34594 at 2.032 0.866 0.014 2.006 1.111 0.214 D 13644 related to the N terminus of tre  34594 at 2.032 0.866 0.014 2.006 1.111 0.214 D 13644 related to the N terminus of tre
35281 at 1.776 0.812 0.024 1.422 0.924 0.038 U31201 laminin, gamma 2 isoform b  35281 at 1.776 0.812 0.024 1.422 0.924 0.038 U31201 laminin, gamma 2 isoform b
35372 r at 1.588 0.72 0.014 1.322 0.811 0.061 M17017 interleukin 8  35372 r at 1.588 0.72 0.014 1.322 0.811 0.061 M17017 interleukin 8
36214 at 1.37 0.592 1 E-04 1.43 0.722 4E-05 画 63 ruppehlike factor 4 (gut)  36214 at 1.37 0.592 1 E-04 1.43 0.722 4E-05 Image 63 ruppehlike factor 4 (gut)
38343 at 1.124 0.543 0.018 0.93 0.947 0.808 AB002326 Alstrom syndrome 1  38343 at 1.124 0.543 0.018 0.93 0.947 0.808 AB002326 Alstrom syndrome 1
38524 at 1.548 0.672 0.024 0.766 1.285 0.091 U49184 occludin 38524 at 1.548 0.672 0.024 0.766 1.285 0.091 U49184 occludin
以上の解析の結果に基づいて、 乾癬の指標とすることができる遺伝子として 次に示す遺伝子を同定した。 これらの遺伝子は、 いずれも本発明における指標 遺伝子として用いることができる。 以下に示す各遺伝子のデータは、 いずれも、 左から順に次の情報を記載している。 各情報はスラッシュ （/) で区切って示し ている。 また指標遺伝子は、 各遺伝子の機能にしたがって、 分類した。 分類さ れた機能を=で示した。 Based on the results of the above analysis, the following genes were identified as genes that can be used as indicators of psoriasis. Any of these genes can be used as an indicator gene in the present invention. Each of the data for each gene shown below lists the following information in order from the left. Each piece of information is separated by a slash (/). Indicator genes were classified according to the function of each gene. The classified functions are indicated by =.
「遺伝子名およびシンボル」  "Gene names and symbols"
「プローブ」 （GeneChipにおけるプローブ ID)  "Probe" (Probe ID in GeneChip)
「プ口ーブの塩基配列のデザィンのために用いられた塩基配列のデータベース (GenBank)ァクセッションナンパー」  "Database of base sequence used for designing base sequence of probe (GenBank) accession number"
「各指標遺伝子の塩基配列のデータベース（GenBank)ァクセッションナンパ一」 「各指標遺伝子によってコードされるァミノ酸配列のデータベース（GenBank)ァ クセッションナンノ 一」  "Base sequence database of each index gene (GenBank) accession database" "Database of amino acid sequence encoded by each indicator gene (GenBank) accession database"
「ReferenCe」 （当該遺伝子を報告した論文、 および塩基配列を配列表に記載し たものについてはその配列番号） “Refer enCe ” (for the paper reporting the gene and the sequence listing of the nucleotide sequence in the sequence listing, its SEQ ID number)
—データ 9 ：  —Data 9:
(アトピー性皮膚炎と乾癬患者の皮疹部における遺伝子発現を、 各患者の無疹 部と比較した結果、 乾癬患者の皮疹部でのみ発現変動/"上昇が認められた遺伝 子）  (Comparison of gene expression in the eruption area of atopic dermatitis and psoriatic patients with the eruption area of each patient indicated that the gene expression was changed / increased only in the eruption area of psoriatic patients)
cellular retinoic acid binding protein 2 I 1057— at / M97815 I NM— 001878 I NP— 001869 I Astrom, A. et al， J. Biol. C em. 267 (35)， 25251-25255 (1 992) cellular retinoic acid binding protein 2 I 1057— at / M97815 I NM— 001878 I NP— 001869 I Astrom, A. et al, J. Biol. C em. 267 (35), 25251-25255 (1992)
proteasome (pro some, macropain) activator subunit 2 / 1184一 at / D45248 I匪— 002818 I NP— 002809 / Joon Young, A. et al, FEBS Lett. 366 (1) , 37—4 2 (1995) proteasome (pro some, macropain) activator subunit 2/1184 at / D45248 I marauder-002818 I NP-002809 / Joon Young, A. et al, FEBS Lett. 366 (1), 37-42 (1995)
interferon induced 6—16 protein isoform a / 1358— s— at / U22970 I NM一 002 038 / P_002029 / Turri, M. G. et al, Nucleic Acids Res. 23 (11)， 1854-18 61 (1995) interferon induced 6—16 protein isoform a / 1358—s—at / U22970 I NM-001 038 / P_002029 / Turri, MG et al, Nucleic Acids Res. 23 (11), 1854-18 61 (1995)
interferon induced 6-16 protein isoform b / 1358一 s一 at / / NM— 022872 / N P一 075010 I Turri. M. G. et al, Nucleic Acids Res. 23 (11)， 1854-1861 (199 5) interferon induced 6-16 protein isoform b / 1358-1 s-1 at / / NM- 022872 / NP-1 075010 I Turri.M.G. et al, Nucleic Acids Res. 23 (11), 1854-1861 (199 5)
interferon induced 6 - 16 protein isoform c / 1358— s一 at / / NM_022873 ·/ N P一 075011 I Turri. M. G. et al, Nucleic Acids Res. 23 (11) , 1854-1861 (199 5) interferon induced 6-16 protein isoform c / 1358-s-1 at / / NM_022873 / N P-1 075011 I Turri.M.G. et al, Nucleic Acids Res. 23 (11), 1854-1861 (199 5)
heat shock 70kDa protein 4 I 1480— at / L12723 I I I Fathallah, D. M. et a 1， J. Immunol. 151 (2) , 810—813 (1993) heat shock 70kDa protein 4 I 1480— at / L12723 I I I Fathallah, D. M. et a 1, J. Immunol. 151 (2), 810—813 (1993)
flap structure— specific endonuc lease 1 / 1516— g— at / / NM一 004111 / NP一 0 04102 I Hiraoka, L. R. et al, Genomics 25 (1) , 220-225 (1995) flap structure— specific endonuc lease 1/1516 — g — at / / NM-1 004111 / NP-1 0 04102 I Hiraoka, L.R. et al, Genomics 25 (1), 220-225 (1995)
NMEl I 1521一 at / X17620 / NM— 000269 / NP— 000260 / Dooley S et al, Hum. Genet. 93 (1)， 63 - 66 (1994) NMEl I 1521 at / X17620 / NM— 000269 / NP— 000260 / Dooley S et al, Hum. Genet. 93 (1), 63-66 (1994)
cyclin— dependent kinase inhibitor 3 / 1599— at / L25876 / NM一 005192 / NP 一 005183 / Poon，R. Y. and Hunter, T. , Science 270 (5233)， 90—93 (1995) ubiquitin - conjugating enzyme E2C / 1651— at / U73379 / NM— 007019 / NP一 00 8950 I Townsley, F. M. et al, Proc. Natl. Acad. Sci. U. S. A. 94 (6)， 2362- 2367 (1997) cyclin— dependent kinase inhibitor 3 / 1599—at / L25876 / NM-005192 / NP-1005183 / Poon, RY and Hunter, T., Science 270 (5233), 90-93 (1995) ubiquitin-conjugating enzyme E2C / 1651— at / U73379 / NM—007019 / NP-00 8950 I Townsley, FM et al, Proc. Natl. Acad. Sci. USA 94 (6), 2362-2367 (1997)
calreticulin / 1752一 at / AD000092 / NM_004343 / NP— 004334 / Rokeach LA et al, J. Immunol. 147 (9) , 3031-3039 (1991) calreticulin / 1752 at / AD000092 / NM_004343 / NP—004334 / Rokeach LA et al, J. Immunol. 147 (9), 3031-3039 (1991)
CDC2 gene / 1803— at / X05360 / NM— 001786 / NP— 001777 / Lee, M. G. and Nur se，P. et al, Nature 327 (6117) , 31—35 (1987)  CDC2 gene / 1803—at / X05360 / NM—001786 / NP—001777 / Lee, MG, and Nurse, P. et al, Nature 327 (6117), 31—35 (1987)
RAN I 1839— at / I 丽—006325 / NP— 006316 / Yokoyama, N. et al, Nature 376 RAN I 1839—at / I 丽 —006325 / NP—006316 / Yokoyama, N. et al, Nature 376
(6536) , 184-188 (1995) (6536), 184-188 (1995)
liver arginase (ARGl) I 1962— at / M14502 / NM— 000045 / NP_000036 I Hara guc i, Y. et al, Proc. Natl. Acad. Sci. U. S. A. 84 (2)， 412-415 (1987) connexin 43 (GJAl, Cx43) / 2018_at / M65188 / NM一 000165 / P_000156 / F ishman, G. I. Et al, J. Cell Biol. Ill (2) , 589-598 (1990) liver arginase (ARGl) I 1962— at / M14502 / NM— 000045 / NP_000036 I Hara guc i, Y. et al, Proc. Natl. Acad. Sci. USA 84 (2), 412-415 (1987) connexin 43 (GJAl, Cx43) / 2018_at / M65188 / NM-000165 / P_000156 / Fishman, GI Et al, J. Cell Biol. Ill (2), 589-598 (1990)
interleukin 1 receptor antagonist / 31343— at / AJ005835 / NM— 000577 / N P— 000568 I一 interleukin 1 receptor antagonist / 31343— at / AJ005835 / NM— 000577 / N P— 000568 I
ATP- binding cassette, sub-family A (ABCl) , member 12 / 31754— at / AL080 207 / NM— 015657 / NP— 056472 I - ATP- binding cassette, sub-family A (ABCl), member 12 / 31754— at / AL080 207 / NM— 015657 / NP— 056472 I-
M - phase phosphoprotein 6 / 31864— at / X98263 / NM— 005792 / NP— 005783 / creatine kinase, mitochondrial 1 I 31887— at / J04469 / NM— 020990 / NP— 0 66270 I Haas, R. C. et al, J. Biol. Chem. 264 (5)， 2890-2897 (1989) Nedd4 binding protein 1 / 32069— at / AB014515 / NM— 014664 / NP— 055479 / solute carrier family 7， member 5 / 32186— at / 80244 / NM— 003486 / P_ 003477 / Gaugitsch, H. W. et al, J. Biol. Chem. 267 (16)， 11267-11273 (19 92) M-phase phosphoprotein 6/31864-at / X98263 / NM-005792 / NP-005783 / creatine kinase, mitochondrial 1 I 31887-at / J04469 / NM-020990 / NP-0 66270 I Haas, RC et al, J. Biol Chem. 264 (5), 2890-2897 (1989) Nedd4 binding protein 1 / 32069—at / AB014515 / NM—014664 / NP—055479 / solute carrier family 7, member 5 / 32186—at / 80244 / NM—003486 / P_ 003477 / Gaugitsch, HW et al, J. Biol. Chem. 267 (16), 11267-11273 (1992)
acid phosphatase, prostate I 32200一 at I M24902 / NM— 001099 / NP— 001090 / Sharief, F. S. et al, Biochem. Biophys. Res. Coramun. 160 (1) , 79-86 (19 89) acid phosphatase, prostate I 32200-I at I M24902 / NM— 001099 / NP— 001090 / Sharief, F.S. et al, Biochem. Biophys. Res.Coramun. 160 (1), 79-86 (19 89)
plakophilin 1 / 32380— at / Z34974 / M_000299 / NP— 000290 / Schmidt, A. et al, Differentiation 64 (5)， 291-306 (1999) plakophilin 1 / 32380—at / Z34974 / M_000299 / NP—000290 / Schmidt, A. et al, Differentiation 64 (5), 291-306 (1999)
UDP glycosyltransferase 1 family, polypeptide A4 / 32392— s— at / M57951 I NM— 007120 I NP— 009051 / Ritter, J. . et al, J. Biol. Chem. 266 (2)， 10 43-1047 (1991)  UDP glycosyltransferase 1 family, polypeptide A4 / 32392-s-at / M57951 I NM-007120 I NP-009051 / Ritter, J.. Et al, J. Biol. Chem. 266 (2), 10 43-1047 (1991)
ATPase, H+ K+ transporting, nongastric, alpha polypeptide / 32482一 at I L42563 I 丽— 001676 / NP— 001667 I Sverdlov, V. E. et al, Genomics 32 (3) , 317-327 (1996) cytoskeleton-associated protein 4 / 32529一 at / X69910 / NM— 006825 / NP一 006816 I - glucosidase, beta; acid / 32632— g— at / J03060 / N _000157 / NP— 000148 / Imai, K. et al, Gene 136 (1-2) , 365-368 (1993) ATPase, H + K + transporting, nongastric, alpha polypeptide / 32482-I at I L42563 I 丽-001676 / NP- 001667 I Sverdlov, VE et al, Genomics 32 (3), 317-327 (1996) cytoskeleton-associated protein 4 / 32529-1 at / X69910 / NM— 006825 / NP-006816 I-glucosidase, beta; acid / 32632— g— at / J03060 / N _000157 / NP— 000148 / Imai, K. et al, Gene 136 (1-2), 365-368 (1993)
interferon-inducible 56 Kd protein I 32814— at / M24594 / NM— 001548 / NP —001539 / Wathelet, M. et al, Eur. J. Biochera. 155 (1)， 11—17 (1986) low density lipoprotein receptor I 32855一 at / L00352 / NM— 000527 / NP一 0 00518 / Russell, D. W. et al, Cell 37 (2) , 577-585 (1984) interferon-inducible 56 Kd protein I 32814— at / M24594 / NM— 001548 / NP — 001539 / Wathelet, M. et al, Eur. J. Biochera. 155 (1), 11-17 (1986) low density lipoprotein receptor I 32 855 at / L00352 / NM—000527 / NP 0 00518 / Russell, DW et al, Cell 37 (2), 577-585 (1984)
transglutaminase 3 I 32868— at / L10386 / NM— 003245 / NP_003236 / Kim, I. G. et al, J. Biol. Chem. 268 (17)， 12682-12690 (1993) transglutaminase 3 I 32868—at / L10386 / NM—003245 / NP_003236 / Kim, IG et al, J. Biol. Chem. 268 (17), 12682-12690 (1993)
arachi donate 12— lipoxygenase, 12R type I 33029— at / AF038461 / NM— 00113 9 I NP一 001130 I Boeglin, W. E. et al, Proc. Natl. Acad. Sci. U. S. A. 95 (1 2) , 6744-6749 (1998) arachi donate 12— lipoxygenase, 12R type I 33029— at / AF038461 / NM— 00113 9 I NP-001130 I Boeglin, WE et al, Proc. Natl. Acad. Sci. USA 95 (1 2), 6744-6749 (1998 )
CYP7B1 / 33055— at I AF029403 / NM— 004820 / NP— 004811 / Setchell, K. D. et al, J. Clin. Invest. 102 (9)， 1690—1703 (1998)  CYP7B1 / 33055—at I AF029403 / NM—004820 / NP—004811 / Setchell, K.D. et al, J. Clin. Invest. 102 (9), 1690—1703 (1998)
tripartite motif-containing 14 isoform alpha / 33253— at / D50919 / NM— 0 14788 I NP— 055603 / - tripartite motif-containing 14 isoform beta / 33253— at / / NM— 033221 I NP— 150090 /― tripartite motif-containing 14 isoform alpha / 33253— at / D50919 / NM— 0 14788 I NP— 055603 /-tripartite motif-containing 14 isoform beta / 33253— at / / NM— 033221 I NP— 150090 / —
hypothetical protein FLJ21168 / 33285— i一 at / W26762 / NM— 025073 / NP一 07 9349 I - heme oxygenase (decycling) 1 / 33802— at / Z82244 / NM— 002133 I NP一 00212 4 / Keyse, S. M. and Tyrrell, R. M. , Proc. Natl. Acad. Sci. U. S. A. 86 (1) , 99-103 (1989) hypothetical protein FLJ21168 / 33285— i-at / W26762 / NM—025073 / NP-07 9349 I-heme oxygenase (decycling) 1 / 33802—at / Z82244 / NM—002133 I NP-002100212 4 / Keyse, SM and Tyrrell, RM, Proc. Natl. Acad. Sci. USA 86 (1), 99-103 (1989)
S100 calcium binding protein P / 34319— at / AA131149 I 匪— 005980 I NP— 0 05971 I Engelkamp, D. et al, Proc. Natl. Acad. Sci. U. S. A. 90 (14) , 654 7-6551 (1993) S100 calcium binding protein P / 34319— at / AA131149 I Marauder — 005980 I NP — 0 05971 I Engelkamp, D. et al, Proc. Natl. Acad. Sci. USA 90 (14), 654 7-6551 (1993)
gene from PAC 747L4 / 34492_at / AL035297 /— /— /一 gene from PAC 747L4 / 34492_at / AL035297 / — / — / one
SAM domain and HD domain 1 I 34714一 at / AL050267 / NM— 015474 / NP_05628 SAM domain and HD domain 1 I 34714 at / AL050267 / NM— 015474 / NP_05628
9 I Li, N. et al, Immunol. Lett. 74 (3) , 221-224 (2000) 9 I Li, N. et al, Immunol. Lett. 74 (3), 221-224 (2000)
arylsulfatase F / 35056一 at / X97868 / NM— 004042 / NP— 004033 / Puca, A. A. et al, Genomics 42 (2) , 192 - 199 (1997) arylsulfatase F / 35056 at / X97868 / NM— 004042 / NP—004033 / Puca, A.A. et al, Genomics 42 (2), 192-199 (1997)
potassium inwardly-rectifying channel, subfamily J, member 15 / 35472— a t I Y10745 I NM一 002243 / NP_002234 / Gosset, P. et al, Genomics 44 (2) , 237-241 (1997) potassium inwardly-rectifying channel, subfamily J, member 15 / 35472-- at t Y10745 I NM-002243 / NP_002234 / Gosset, P. et al, Genomics 44 (2), 237-241 (1997)
BUBl budding uninhibited by benz imidazoles 1 homolog beta (yeast) / 356 99— at I AF053306 / NM— 001211 I NP一 001202 / Taylor, S. S. et al, J. Cell B iol. 142 (1)， 1-11 (1998)  BUBl budding uninhibited by benz imidazoles 1 homolog beta (yeast) / 356 99— at I AF053306 / NM— 001211 I NP-001202 / Taylor, SS et al, J. Cell Biol. 142 (1), 1-11 (1998 )
SPllO nuclear body protein isoform b / 35718一 at / L22342 / NM— 004510 / NP一 004501 I adereit, S. et al, J. Biol. Chem. 268 (32) , 24432-24441 (19 93)  SPllO nuclear body protein isoform b / 35718 at / L22342 / NM—004510 / NP-004501 I adereit, S. et al, J. Biol. Chem. 268 (32), 24432-24441 (19 93)
guanylate binding protein 1 (GBPl) / 35735一 at / M55542 / NM_002053 / NP —002044 I Strehlow, I. Et al, Gene 144 (2)， 295-299 (1994) guanylate binding protein 1 (GBPl) / 35,735 at / M55542 / NM_002053 / NP—002044 I Strehlow, I. Etal, Gene 144 (2), 295-299 (1994)
GM2 ganglioside activator protein / 35820一 at / X62078 I NM_000405 / NP一 000396 / Xie, B. et al, Biochem. Biophys. Res. Comraun. 177 (3)， 1217-122 3 (1991) GM2 ganglioside activator protein / 35820 at / X62078 I NM_000405 / NP 000396 / Xie, B. et al, Biochem. Biophys. Res. Comraun. 177 (3), 1217-1223 (1991)
complement factor B preproprotein / 35822— at / L15702 / NM一 001710 / NP— 001701 / Campbell, R. D. and Porter, R. R. , Proc. Natl. Acad. Sci. U. S. A. 8complement factor B preproprotein / 35822—at / L15702 / NM-001710 / NP—001701 / Cambell, R.D. and Porter, R.R., Proc. Natl. Acad. Sci. U.S.A. 8
0 (14) , 4464-4468 (1983) 0 (14), 4464-4468 (1983)
squalene epoxidase I 35839— at / D78130 /画一 003129 I NP一 003120 / Ladensqualene epoxidase I 35839- at / D78130 / 1 003129 I NP 1 003120 / Laden
BP et al, Arch. Biochem. Biophys. 374 (2) , 381—388 (2000) BP et al, Arch. Biochem. Biophys. 374 (2), 381-388 (2000)
solute carrier family 5 (sodium glucose cotransporter) , member 1 I 3590
Figure imgf000276_0001
solute carrier family 5 (sodium glucose cotransporter), member 1 I 3590
Figure imgf000276_0001
6— at I L29339 / NM— 000343 / NP— 000334 / Turk, E. et al, J. Biol. Chem. 2 69 (21) , 15204-15209 (1994)  6 at I L29339 / NM-000343 / NP-000334 / Turk, E. et al, J. Biol. Chem. 269 (21), 15204-15209 (1994)
ZWIO interactor Zwint variant 1 I 35995— at / AF067656 / NM— 007057 / P_ 008988 / Starr, D. A. et al, J. Cell. Sci. 113 (Pt 11) , 1939-1950 (2000) ZWIO interactor Zwint variant 2 / 35995一 at / AF067656 / NM一 032997 / NP— 127490 I Starr, D. A. et al, J. Cell. Sci. 113 (Pt 11)， 1939—1950 (2000) kallikrein 13 / 36406一 at / AA401397 / NM_015596ノ NP— 056411 / Gan, L. et al, Gene 257 (1)， 119-130 (2000)  ZWIO interactor Zwint variant 1 I 35995—at / AF067656 / NM—007057 / P_008988 / Starr, DA et al, J. Cell.Sci. 113 (Pt 11), 1939-1950 (2000) ZWIO interactor Zwint variant 2/35995 1 at / AF067656 / NM 032997 / NP- 127490 I Starr, DA et al, J. Cell. Sci. 113 (Pt 11), 1939-1950 (2000) kallikrein 13/36406 1 at / AA401397 / NM_015596 NP- 056411 / Gan, L. et al, Gene 257 (1), 119-130 (2000)
interferon regulatory factor 7 isoform a / 36412_s_at / U53830 / NM一 001 572 I NP一 001563 / - interferon regulatory factor 7 isoform b / 36412一 s一 at / U53831 / NM— 004 029 I NP-004020 / - interferon regulatory factor 7 isoform d / 36412_s_at / AF076494 / NM一 0 04031 I NP— 004022 /― interferon regulatory factor 7 isoform a / 36412_s_at / U53830 / NM-001 572 I NP- 001563 /-interferon regulatory factor 7 isoform b / 36412-s at at / U53831 / NM- 004 029 I NP-004020 /-interferon regulatory factor 7 isoform d / 36412_s_at / AF076494 / NM 0 04031 I NP- 004022 /-
interferon regulatory factor 7， transcript variant c / 36412一 s— at / U53 832 I NM— 004030 / NP— 004021 /一 interferon regulatory factor 7, transcript variant c / 36412 s-at / U53 832 I NM-004030 / NP-004021 / ichi
N-myc (and STAT) interactor / 36472— at / U32849 / NM— 004688 / NP— 004679 N-myc (and STAT) interactor / 36472—at / U32849 / NM—004688 / NP—004679
I Bao, J. and Zervos, A. S. , Oncogene 12 (10) , 2171-2176 (1996) I Bao, J. and Zervos, A.S., Oncogene 12 (10), 2171-2176 (1996)
Stat2 I 36770— at I U18671 I NM— 005419 / NP— 005410 / Yan, R. et al, Nucle ic Acids Res. 23 (3)， 459-463 (1995) Stat2 I 36770—at I U18671 I NM—005419 / NP—005410 / Yan, R. et al, Nucleic Acids Res. 23 (3), 459-463 (1995)
tripartite motif-containing 22 / 36825— at / X82200 / NM— 006074 I NP一 006 065 / Tissot, C. and Mechti. N. et al, J. Biol. Chem. 270 (25) , 14891 - 148 98 (1995) tripartite motif-containing 22 / 36825—at / X82200 / NM—006074 I NP-006 065 / Tissot, C. and Mechti.N. et al, J. Biol. Chem. 270 (25), 14891-148 98 (1995 )
kinesin— like 6 / 36837— at / U63743 /匪—006845 / NP— 006836 / Kim, I. G. e t al, Biochim. Biophys. Acta 1359 (3) , 181-186 (1997) kinesin—like 6 / 36837—at / U63743 / Marauder—006845 / NP—006836 / Kim, I.G. et al, Biochim.Biophys. Acta 1359 (3), 181-186 (1997)
kallikrein 10 variants 1 / 36838 at / AF055481 / NM— 002776 / NP— 002767 / Luo, L. et al, Biochem. Biophys. Res. Commun. 247 (3)， 580-586 (1998) kallikrein 10 variants 2 I 36838— at / AF055481 / NM— 145888 / NP— 665895 / Luo, L. et al, Biochem. Biophys. Res. Commun. 247 (3) , 580 - 586 (1998) ribonucleotide reductase M2 polypeptide / 36922— at / X59618 / N一 001034kallikrein 10 variants 1/36838 at / AF055481 / NM— 002776 / NP— 002767 247 (3), 580-586 (1998) kallikrein 10 variants 2 I 36838—at / AF055481 / NM—145888 / NP—665895 / Luo, L. / Luo, L. et al, Biochem. Biophys. Res. 247 (3), 580-586 (1998) ribonucleotide reductase M2 polypeptide / 36922—at / X59618 / N-001034 et al, Biochem. Biophys. Res.
I NP— 001025 I Pavlof f, N. et al, DNA Seq. 2 (4) , 227-234 (1992) I NP— 001025 I Pavlof f, N. et al, DNA Seq. 2 (4), 227-234 (1992)
chromosome 1 open reading frame 29 / 36927— at / AB000115 / NM— 006820 / NP一 006811 I -chromosome 1 open reading frame 29 / 36927— at / AB000115 / NM— 006820 / NP-006811 I-
Sjogren syndrome antigen Al / 37126一 at / M62800 / NM— 003141 / NP— 003132Sjogren syndrome antigen Al / 37126 at / M62800 / NM—003141 / NP—003132
I Chan, E. K. et al, J. Clin. Invest. 87 (1) , 68—76 (1991) I Chan, E. K. et al, J. Clin. Invest. 87 (1), 68--76 (1991)
gamma - glutamyl hydrolase / 37263— at / U55206 / NM— 003878 / NP— 003869 / Yao, R. et al, Proc. Natl. Acad. Sci. U. S. A. 93 (19) , 10134 - 10138 (1996) lymphocyte antigen 6 complex, locus E / 37360一 at / U66711 / NM_002346 / NP一 002337 I Capone, M. C. et al, J. Immunol. 157 (3) , 969—973 (1996) interleukin-1 receptor antagonist / 37603一 at / X52015 / NM— 000577 / NP一 000568 I - interferon— induced protein 44 I 37641— at / D28915 / NM— 006417 / NP— 0064 08 I Kitamura, A. et al, Eur. J. Biochem. 224 (3)， 877—883 (1994) lectin, galactoside-binding, soluble, 3 binding protein / 37754— at / LI 3210 I NM— 005567 / NP— 005558 / Koths, K. et al, J. Biol. Chem. 268 (19) , 14245-14249 (1993) gamma-glutamyl hydrolase / 37263-at / U55206 / NM-003878 / NP-003869 / Yao, R. et al, Proc. Natl. Acad. Sci. USA 93 (19), 10134-10138 (1996) lymphocyte antigen 6 complex , locus E / 37360 at / U66711 / NM_002346 / NP-1002337 I Capone, MC et al, J. Immunol. 157 (3), 969-973 (1996) interleukin-1 receptor antagonist / 37603 at / X52015 / NM — 000577 / NP-000568 I-interferon—induced protein 44 I 37641—at / D28915 / NM—006417 / NP—006408 I Kitamura, A. et al, Eur. J. Biochem. 224 (3), 877—883 (1994) lectin, galactoside-binding, soluble, 3 binding protein / 37754- at / LI 3210 I NM-005567 / NP-005558 / Koths, K. et al, J. Biol. Chem. 268 (19), 14245- 14249 (1993)
retinoblastoma binding protein 6 / 38265一 at / AI538172 / NM_006910 / NP 一 008841 I Sakai, Y. et al, Genomics 30 (1) , 98-101 (1995) retinoblastoma binding protein 6/38265 at / AI538172 / NM_006910 / NP 008841 I Sakai, Y. et al, Genomics 30 (1), 98-101 (1995)
vipirin / 38549— at I AF026941 I 醒— 080657 / NP— 542388 / Chin, K. C. and C resswell, P. , Proc. Natl. Acad. Sci. U. S. A. 98 (26) , 15125-15130 (2001) interferon - induced protein with tetratricopeptide repeats 4 / 38584— at I AF026939 I 匪— 001549 / NP一 001540 / Yu, M. et al, Proc. Natl. Acad. Sci. 2 7 7し―：— vipirin / 38549— at I AF026941 I Awake — 080657 / NP— 542388 / Chin, KC and C resswell, P., Proc. Natl. Acad. Sci. USA 98 (26), 15125-15130 (2001) interferon-induced protein with tetratricopeptide repeats 4 / 38584— at I AF026939 I Marauder — 001549 / NP-001540 / Yu, M. et al, Proc. Natl. Acad. Sci. 2 7 7
U. S. A. 94 (14)， 7406-7411 (1997)  U.S.A. 94 (14), 7406-7411 (1997)
S100 calcium binding protein A12 (calgranulin C) / 38879一 at / D83664 / NM一 005621 I NP一 005612 I Wicki, R. et al, Cell Calcium 20 (6) , 459-464 (1 996) S100 calcium binding protein A12 (calgranulin C) / 38879-1 at / D83664 / NM 005621 I NP 005612 I Wicki, R. et al, Cell Calcium 20 (6), 459-464 (1 996)
bone marrow stromal cell antigen 2 / 39061一 at / D28137 / NM一 004335 / NP 一 004326 I Ishikawa, J. et al, Genomics 26 (3)， 527—534 (1995) bone marrow stromal cell antigen 2/39061 at / D28137 / NM 004335 / NP 004326 I Ishikawa, J. et al, Genomics 26 (3), 527-534 (1995)
chromosome 20 open reading frame 1 / 39109一 at / AB024704 / l_012112 / NP— 036244 /一 chromosome 20 open reading frame 1/39109 ichi at / AB024704 / l_012112 / NP— 036244 / ichi
aquaporin 3 / 39249— at / AB001325 / NM— 004925 / NP— 004916 / Ishibashi, K. et al, Genomics 27 (2) , 352-354 (1995) aquaporin 3 / 39249—at / AB001325 / NM—004925 / NP—004916 / Ishibashi, K. et al, Genomics 27 (2), 352-354 (1995)
cystatin A (stefin A) I 39581一 at / AA570193 / 應—005213 / NP— 005204 / Y amazaki, M. et al, DNA Seq. 8 (1—2)， 71-76 (1997) cystatin A (stefin A) I 39581 at / AA570193 / O-005213 / NP-005204 / Yamazaki, M. et al, DNA Seq. 8 (1-2), 71-76 (1997)
KIAA0186 I 39677— at / D80008 / NM_021067 / NP— 066545 / Nagase, T. et al, KIAA0186 I 39677—at / D80008 / NM_021067 / NP—066545 / Nagase, T. et al,
DNA Res. 3 (1) , 17-24 (1996) DNA Res. 3 (1), 17-24 (1996)
retinoblastoma - associated protein HEC / 40041— at / AF017790 / NM— 006101retinoblastoma-associated protein HEC / 40041—at / AF017790 / NM—006101
I NP一 006092 I Chen, Y. et al, Mol. Cell. Biol. 17 (10)， 6049-6056 (199 7) I NP-006092 I Chen, Y. et al, Mol. Cell. Biol. 17 (10), 6049-6056 (199 7)
NSl - associated protein 1 I 40122— at / AF037448 / NM— 006372 / NP— 006363 I Harris, C. E. et al, J. Virol. 73 (1)， 72 - 80 (1999)  NSl-associated protein 1 I 40122— at / AF037448 / NM— 006372 / NP— 006363 I Harris, C. E. et al, J. Virol. 73 (1), 72-80 (1999)
topoisomerase (DNA) II alpha 170kDa / 40145— at / AI375913 / NM— 001067 / NP一 001058 / Chung, T. D. et al, Proc. Natl. Acad. Sci. U. S. A. 86 (23) , 9 431-9435 (1989) topoisomerase (DNA) II alpha 170kDa / 40145- at / AI375913 / NM-001067 / NP-001058 / Chung, T. D. et al, Proc. Natl. Acad. Sci. U.S.A. 86 (23), 9 431-9435 (1989)
H2A histone family, member X / 40195— at / X14850 / 丽—002105 I NP— 00209 6 I Mannironi, C. et al, Nucleic Acids Res. 17 (22) , 9113-9126 (1989) chemokine exodus— 1 I 40385一 at / U64197 / 丽—004591 / NP— 004582 / Hromas, R. et al.， Blood 89 (9)， 3315—3322 (1997) pituitary tumor-transforming 1 / 40412— at / AA203476 / NM一 004219 / NP一 0 04210 I Zhang, X. et al, MoL Endocrinol. 13 (1 156-166 (1999) H2A histone family, member X / 40195—at / X14850 / 丽 —002105 I NP— 00209 6 I Mannironi, C. et al, Nucleic Acids Res. 17 (22), 9113-9126 (1989) chemokine exodus— 1 I 40385 At / U64197 / 丽 —004591 / NP—004582 / Hromas, R. et al., Blood 89 (9), 3315—3322 (1997) pituitary tumor-transforming 1 / 40412-at / AA203476 / NM-004219 / NP-1 0 04210 I Zhang, X. et al, MoL Endocrinol. 13 (1 156-166 (1999)
SCO cytochrome oxidase deficient homo log 2 (yeast) / 40639一 at / AL02168 3 I NM— 005138 / NP一 005129 I Papadopoulou, L. C. et al, Nat. Genet. 23 (3 333-337 (1999) SCO cytochrome oxidase deficient homo log 2 (yeast) / 40 639 at / AL02168 3 I NM— 005138 / NP 005129 I Papadopoulou, L.C. et al, Nat.Genet. 23 (3 333-337 (1999)
CDC28 protein kinase regulatory subunit 2 / 40690— at / X54942 / NM— 0018 27 I NP一 001818 I Richardson, H. E. et al, Genes Dev. 4 (8 1332-1344 (19 90)  CDC28 protein kinase regulatory subunit 2 / 40690—at / X54942 / NM—001827 I NP-1 001818 I Richardson, H.E. et al, Genes Dev. 4 (8 1332-1344 (19 90)
kinesin— like 1 / 40726一 at I U37426 / NM_004523 / NP一 004514 / Blangy, A. et al, Cell 83 (7 1159—1169 (1995) kinesin- like 1 / 40726-I at I U37426 / NM_004523 / NP-004514 / Blangy, A. et al, Cell 83 (7 1159-1169 (1995)
histidine onia— lyase / 40735— at / D16626 / NM_002108 / NP— 002099 / S uchi, M. et al, Biochim. Biophys. Acta 1216 (2 293-295 (1993) histidine onia— lyase / 40735— at / D16626 / NM_002108 / NP — 002099 / Suchi, M. et al, Biochim. Biophys. Acta 1216 (2 293-295 (1993)
hypothetical protein FLJ10534 I 40982一 at / AA926957 / NM— 018128 I NP一 06 0598 I一 hypothetical protein FLJ10534 I 40982 one at / AA926957 / NM— 018128 I NP one 06 0598 I one
cyclin El isoform 1 / 41060一 at / 74093 / ML001238 / NP— 001229 I Sewin g, A. et al, J. Cell. Sci. 107 (Pt 2) , 581-588 (1994) cyclin El isoform 1/41060 at / 74093 / ML001238 / NP—001229 I Sewing, A. et al, J. Cell.Sci. 107 (Pt 2), 581-588 (1994)
cyclin El isoform 2 / 41060— at / M74093 I NM— 057182 / NP_476530 / Sewin g, A. et al, J. Cell. Sci. 107 (Pt 2) , 581 - 588 (1994) cyclin El isoform 2 / 41060— at / M74093 I NM— 057182 / NP_476530 / Sewin g, A. et al, J. Cell. Sci. 107 (Pt 2), 581-588 (1994)
chromosome 1 open reading frame 34 / 41680一 at / AF007170 I I I Kuang, W. W. et al, Nucleic Acids Res. 26 (4) , 1116 - 1123 (1998) chromosome 1 open reading frame 34/41680 ichi at / AF007170 I I I Kuang, W. W. et al, Nucleic Acids Res. 26 (4), 1116-1123 (1998)
TTK protein kinase I 572一 at / M86699 / NM— 003318 / NP_003309 / Mills, G. B. et al, J. Biol. Chem. 267 (22) , 16000 - 16006 (1992) TTK protein kinase I 572 at / M86699 / NM—003318 / NP_003309 / Mills, GB.et al, J. Biol. Chem. 267 (22), 16000-16006 (1992)
interleukin 8 receptor beta (IL8RB) / 664一 at / L19593 / NM— 001557 / NP一 001548 I Sprenger H et al, J. Biol. Chem. 269 (15) , 11065-11072 (1994) RAB27A I 809— at / U57094 / 匪— 004580 / NP— 004571 / Tolmachova, T, et al, Gene 239 (1) , 109-116 (1999) MX2 I 879— at / M30818 I NM— 002463 / NP一 002454 / Horisberger, M. A. et al, J. Virol. 64 (3)， 1171 - 1181 (1990) interleukin 8 receptor beta (IL8RB) / 664 at / L19593 / NM- 001557 / NP 001548 I Sprenger H et al, J. Biol. Chem. 269 (15), 11065-11072 (1994) RAB27A I 809— at / U57094 / Marauder— 004580 / NP— 004571 / Tolmachova, T, et al, Gene 239 (1), 109-116 (1999) MX2 I 879—at / M30818 I NM—002463 / NP-1002454 / Horisberger, MA et al, J. Virol. 64 (3), 1171-1181 (1990)
thymidine kinase 1 I 910— at / M15205 / NM— 003258 / NP— 003249 / Flemingt on E et al, Gene 52 (2-3) , 267-277 (1987) thymidine kinase 1 I 910—at / M15205 / NM—003258 / NP—003249 / Flemingt on E et al, Gene 52 (2-3), 267-277 (1987)
interferon-inducible 56kd protein / 915一 at / M24594 /一 /一 /一 serum glucocorticoid regulated kinase / 973一 at / Y10032 / NM一 005627 / Ninterferon-inducible 56kd protein / 915 at / M24594 / one / one / one serum glucocorticoid regulated kinase / 973 at / Y10032 / NM one 005627 / N
P— 005618 I -P— 005618 I-
EphA2 I 1379_at / M59371 / NM_004431 / NP— 004422 / Lindberg, R. A. and Hu nter, T. et al, Mol. Cell. Biol. 10 (12) , 6316-6324 (1990) EphA2 I 1379_at / M59371 / NM_004431 / NP— 004422 / Lindberg, R.A. and Hunter, T. et al, Mol. Cell. Biol. 10 (12), 6316-6324 (1990)
nitric oxide synthase 2A I 1948一 f— at / U31511 / NM— 000625 / NP— 000616 /nitric oxide synthase 2A I 1948 one f—at / U31511 / NM—000625 / NP—000616 /
Charles, I. G. et al, Proc. Natl. Acad. Sci. U. S. A. 90 (23) , 11419—11423Charles, I.G. et al, Proc. Natl. Acad. Sci. U.S.A. 90 (23), 11419—11423
(1993) (1993)
plasminogen activator, tissue type isoform 1 preproprotein / 33452一 at / M15518 I NM— 000930 / NP— 000921 / Harris, T. J. et al, Mol. Biol. Med. 3 (3) , 279-292 (1986) plasminogen activator, tissue type isoform 1 preproprotein / 33452-1 at / M15518 I NM— 000930 / NP—000921 / Harris, T. J. et al, Mol. Biol. Med. 3 (3), 279-292 (1986)
plasminogen activator, tissue type isoform 2 precursor / 33452一 at / X13 097 I NM— 000931 I NP一 000922 / Harris, T. J. et al, Mol. Biol. Med. 3 (3)， 279—292 (1986) plasminogen activator, tissue type isoform 2 precursor / 33452 at / X13 097 I NM— 000931 I NP 000922 / Harris, T. J. et al, Mol. Biol. Med. 3 (3), 279—292 (1986)
plasminogen activator, tissue type isoform 3 precursor / 33452— at I X13 097 I NM一 033011 I NP— 127509 I Harris, T. J. et al, Mol. Biol. Med. 3 (3) , 279-292 (1986) plasminogen activator, tissue type isoform 3 precursor / 33452— at I X13 097 I NM-1 0 33011 I NP— 127509 I Harris, T. J. et al, Mol. Biol. Med. 3 (3), 279-292 (1986)
KIAA0963 protein / 36336—s— at I AC005390 / NM— 014963 / NP— 055778 I一 KIAA0963 protein / 36336—s— at I AC005390 / NM— 014963 / NP— 055778 I
Kallikrein 13 / 36407— at I AL050220 / - / - / -Kallikrein 13 / 36407—at I AL050220 /-/-/-
ATPase Class V, type 10B / 37415_at I AB018258 /— /— /— ATPase Class V, type 10B / 37415_at I AB018258 / — / — / —
GART I 38384— at I X54199 I匪— 000819 / NP— 000810 / Aimi, J. et al, Nucle ic Acids Res. 18 (22) , 6665-6672 (1990) 一データ 1 0 ： GART I 38384—at I X54199 I Marauder—000819 / NP—000810 / Aimi, J. et al, Nucleic Acids Res. 18 (22), 6665-6672 (1990) One data 10:
(ァトピー性皮膚炎と乾癬患者の皮疹部における遺伝子発現を各患者の無疹部 と比較した結果、 乾癬患者の皮疹部でのみ発現変動/低下が認められた遺伝 チ）  (Comparison of gene expression in atopic dermatitis and rash in psoriatic patients with non-rash in each patient revealed that the expression was fluctuated / reduced only in the rash in psoriatic patients)
actin, gamma 2, smooth muscle, enteric /1197一 at /D00654 /NM一 001615 /NP_ 001606 /Miwa, T. et al, Nucleic Acids Res. 18 (14) , 4263 (1990) cisplatin resistance associated /1229一 at /U78556 /Ml— 006697 /NP— 006688 /- hypothetical gene CG018 /1527— s— at /U50527 /NM— 052818 /NP— 438169 /- growth arrest-specific 6 /1597_at /L13720 /應— 000820 /NP_000811 /Manfi oletti, G. et al, Mol. Cell. Biol. 13 (8) , 4976-4985 (1993) actin, gamma 2, smooth muscle, enteric / 1197-1 at / D00654 / NM-1 001615 / NP_ 001606 / Miwa, T. et al, Nucleic Acids Res. 18 (14), 4263 (1990) cisplatin resistance associated // 1229-1 at / U78556 / Ml— 006697 / NP— 006688 /-hypothetical gene CG018 / 1527— s— at / U50527 / NM— 052818 / NP— 438169 /-growth arrest-specific 6 / 1597_at / L13720 / O—000820 / NP_000811 / Manfi oletti, G. et al, Mol.Cell.Biol. 13 (8), 4976-4985 (1993)
insulin-like growth factor binding protein 6 /1736一 at /M62402 /NM— 00217 8 /NP一 002169 /Kief er, M. C. et al, J. Biol. Chem. 266 (14) , 9043-9049 (1 991) insulin-like growth factor binding protein 6 / 1736-at / M62402 / NM- 00217 8 / NP-002169 / Kiefer, M.C. et al, J. Biol.Chem. 266 (14), 9043-9049 (1 991)
platelet-derived growth factor receptor-like /1761一 at /D37965 /NM— 00620 7 /NP一 006198 /Fujiwara, Y. et al, Oncogene 10 (5)， 891—895 (1995) related RAS viral (r~ras) oncogene homolog /1879—at / 14949 /NM— 006270 /NP— 006261 /Lowe, D. G. et al, Cell 48 (1) , 137-146 (1987) platelet-derived growth factor receptor-like / 1761 at / D37965 / NM— 00620 7 / NP-006198 / Fujiwara, Y. et al, Oncogene 10 (5), 891—895 (1995) related RAS viral (r ~ ras ) oncogene homolog / 1879-at / 14949 / NM- 006270 / NP- 006261 / Lowe, DG et al, Cell 48 (1), 137-146 (1987)
fibroblast growth factor receptor 1, isoform 1 /2057_g_at /M34641 /NM— 0 00604 /NP— 000595 /- fibroblast growth factor receptor 1, isoform 2 /2057一 g一 at /M34641 /NM— 0 15850 /NP— 056934 /- fibroblast growth factor receptor 1, isoform 3 /2057—g—at /M34641 /匪一 0fibroblast growth factor receptor 1, isoform 1 / 2057_g_at / M34641 / NM— 0 00604 / NP— 000595 /-fibroblast growth factor receptor 1, isoform 2/2057 per g at / M34641 / NM— 0 15850 / NP— 056934 /- fibroblast growth factor receptor 1, isoform 3 / 2057—g—at / M34641 / martial one 0
23105 /NP— 075593 /- fibroblast growth factor receptor 1, isoform 4 /2057_g_at /M34641 /蘭—023105 / NP— 075593 /-fibroblast growth factor receptor 1, isoform 4 / 2057_g_at / M34641 / Ran-0
23106 /NP— 075594 /_ 2 8 l| ： 23106 / NP— 075594 / _ 2 8 l |:
fibroblast growth factor receptor 1, isoform 7 /2057_g_at /M34641 /NM一 0 23109 / P_075597 /- fibroblast growth factor receptor 1, isoform 9 /2057_g_at /M34641 /NM一 0 23111 /NP_075599 /- fibronectin 1 isoform 1 preproprotein /311— s— at /M15801 /NM— 002026 /NP一 002017 /- chromosome 21 open reading frame 25 /32107— at /AL050173 /AL833323 /- /- seven in absentia homolog 1 (Drosophila) /32161一 at / 26406 /NM— 003031 / NP— 003022 /Nemani, M. et al, Proc. Natl. Acad. Sci. U. S. A. 93 (17)， 903 9-9042 (1996) fibroblast growth factor receptor 1, isoform 7 / 2057_g_at / M34641 / NM-0 23109 / P_075597 /-fibroblast growth factor receptor 1, isoform 9 / 2057_g_at / M34641 / NM-1 0 23111 / NP_075599 /-fibronectin 1 isoform 1 preproprotein / 311— s—at / M15801 / NM—002026 / NP-002017 / -chromosome 21 open reading frame 25 / 32107—at / AL050173 / AL833323 /-/-seven in absentia homolog 1 (Drosophila) / 32161-at / 26406 / NM— 003031 / NP— 003022 / Nemani, M. et al, Proc. Natl. Acad. Sci. USA 93 (17), 903 9-9042 (1996)
fatty acid desaturase 2 /32190— at /AL050118 /NM— 004265 /NP— 004256 /Cho, H. P. et al, J. Biol. Chem. 274 (1)， 471—477 (1999) fatty acid desaturase 2 / 32190—at / AL050118 / NM—004265 / NP—004256 / Cho, H.P. et al, J. Biol. Chem. 274 (1), 471—477 (1999)
Rho- related BTB domain containing 3 /32215— i— at /AB020685 /NM— 014899 /N P— 055714 /- matrilin 2 variant 1 /32239_at /U69263 /NM— 002380 /NP— 002371 /Deak, F. et al, J. Biol. Chem. 272 (14) , 9268-9274 (1997)  Rho-related BTB domain containing 3 / 32215— i— at / AB020685 / NM— 014899 / NP— 055714 /-matrilin 2 variant 1 / 32239_at / U69263 / NM— 002380 / NP— 002371 / Deak, F. et al, J . Biol. Chem. 272 (14), 9268-9274 (1997).
matrilin 2 variant 2 /32239_at /U69263 /NM— 030583 /NP— 085072 /Deak, F. et al, J. Biol. Chem. 272 (14) , 9268-9274 (1997) matrilin 2 variant 2 / 32239_at / U69263 / NM— 030583 / NP— 085072 / Deak, F. et al, J. Biol. Chem. 272 (14), 9268-9274 (1997)
adipose specific 2 /32527_at /AI381790 /NM— 006829 /NP_006820 /Maeda, K. et al, Biochem. Biophys. Res. Co画 n. 221 (2) , 286-289 (1996) adipose specific 2 / 32527_at / AI381790 / NM— 006829 / NP_006820 / Maeda, K. et al, Biochem.Biophys.Res. Co. n. 221 (2), 286-289 (1996)
four and a half LIM domains 1 /32542_at /AF063002 /NM一 001449 /NP— 001440four and a half LIM domains 1 / 32542_at / AF063002 / NM-001449 / NP— 001440
/Lee, S. M. et al, Gene 216 (1) , 163 - 170 (1998) / Lee, S.M. et al, Gene 216 (1), 163-170 (1998)
myosin light chain kinase isoform 6 /32847_at /X85337 /丽— 005965 /NP一 00 5956 /- myosin light chain kinase isoform 1 /32847_at /U48959 /蘭一 053025 /NP一 44 4253 /- myosin light chain kinase isoform 2 /32847_at /AF069601 /匪一 053026 /NP一 444254 /- myosin light chain kinase isoform 3A /32847— at /AF069602 /NM— 053027 /NP 一 444255 /- myosin light chain kinase isoform 3B /32847_at /AF069603 /NM— 053028 /NP 一 444256 /- myosin light chain kinase isoform 4 /32847_at /U48959 / L053029 /NP— 44 4257 /一 myosin light chain kinase isoform 6 / 32847_at / X85337 / 丽 —005965 / NP-00 5956 /-myosin light chain kinase isoform 1 / 32847_at / U48959 / Ranichi 053025 / NP-44 4253 /- myosin light chain kinase isoform 2 / 32847_at / AF069601 / marauder 053026 / NP-1 444254 /-myosin light chain kinase isoform 3A / 32847— at / AF069602 / NM— 053027 / NP-1 444255 /-myosin light chain kinase isoform 3B / 32847_at / AF069603 / NM— 053028 / NP-444256 /-myosin light chain kinase isoform 4 / 32847_at / U48959 / L053029 / NP—44 4257 / one
myosin light chain kinase isoform 5 /32847_at /AB037663 /NM一 053030 /NP一 444258 /- kinase related protein, telokin isoform 7 /32847_at /U48959 /NM— 053031 /NP— 444259 /- kinase related protein, telokin isoform 8 /32847_at /請 959 /NM— 053032 /NP一 444260 /- cysteine- rich protein 1 (intestinal) /33232_at /AI017574 /NM— 001311 /NP 一 001302 /Tsui, S. K. et al, Biochem. Biophys. Res. Comraun. 205 (1)， 497—5 05 (1994) myosin light chain kinase isoform 5 / 32847_at / AB037663 / NM-1 053030 / NP-1 444258 /-kinase related protein, telokin isoform 7 / 32847_at / U48959 / NM— 053031 / NP— 444259 /-kinase related protein, telokin isoform 8 / 32847_at / Contract 959 / NM- 053032 / NP-444260 /-cysteine-rich protein 1 (intestinal) / 33232_at / AI017574 / NM- 001311 / NP-001302 / Tsui, SK et al, Biochem. Biophys. Res. Comraun. 205 ( 1), 497-5 05 (1994)
sarcospan (Kras oncogene - associated gene) /33303一 at /N21470 /NM— 005086 /NP一 005077 /Crosbie, R. H. et al, J. Biol. Chem. 272 (50) , 31221-31224 (1997) sarcospan (Kras oncogene-associated gene) / 33303 at / N21470 / NM- 005086 / NP-005077 / Crosbie, R.H. et al, J. Biol. Chem. 272 (50), 31221-31224 (1997)
KIAA0367 gene /33442_at /AB002365 /— /- /一  KIAA0367 gene / 33442_at / AB002365 / — /-/ one
amine oxidase, copper containing 3 (vascular adhesion protein 1) /33756 —at /U39447 /NM_003734 /NP— 003725 /Zhang, X. et al, Gene 179 (2)， 279— 286 (1996) amine oxidase, copper containing 3 (vascular adhesion protein 1) / 33756 —at / U39447 / NM_003734 / NP— 003725 / Zhang, X. et al, Gene 179 (2), 279—286 (1996)
chemokine (C-C motif) ligand 14, isoform 1 /33790— at /AI720438 /顧— 0041 66 /NP_004157 /一 chemokine (C— C motif) ligand 14， isoform 2 /33790_at /AI720438 /NM— 0329 62 /NP_116738 /-chemokine (CC motif) ligand 14, isoform 1 / 33790—at / AI720438 / customer— 0041 66 / NP_004157 / one chemokine (C—C motif) ligand 14, isoform 2 / 33790_at / AI720438 / NM—0329 62 / NP_116738 /-
FLJ13612 /33878— at /W27472 /NM_025202 /NP_079478 /Tominaga, M. et al, Bi ochem. Biophys. Res. Co顧 n. 297 (3) , 473-479 (2002) FLJ13612 / 33878—at / W27472 / NM_025202 / NP_079478 / Tominaga, M. et al, Biochem. Biophys. Res.Co Co. n. 297 (3), 473-479 (2002)
ocular development-associated gene /34196— at /AI337901 /NM一 021167 /NP_0 66990 /Tsuruga, T. et al, Gene 290 (1-2)， 125-130 (2002) ocular development-associated gene / 34196—at / AI337901 / NM-I 021167 / NP_0 66990 / Tsuruga, T. et al, Gene 290 (1-2), 125-130 (2002)
FLJ90798 /34303— at /AL049949 /應— 153367 /NP一 699198 /- ephrin-B2 /34335_at /AI765533 /NM_004093 /NP— 004084 /Cerretti DP et al, Mol. Immunol. 32 (16) , 1197-1205 (1995) FLJ90798 / 34303—at / AL049949 / O—1533367 / NP-699198 / -ephrin-B2 / 343335_at / AI765533 / NM_004093 / NP—004084 / Cerretti DP et al, Mol. Immunol. 32 (16), 1197-1205 (1995) )
Na, K-ATPase subunit alpha 2 (ATP1A2) /34377— at /J05096 /NM_000702 / P_0 00693 /Shull, M. M. et al, J. Biol. Chem. 264 (29)， 17532-17543 (1989) aquaporin 9 /34435— at /AB008775 /蘭— 020980 /NP— 066190 /Ishibashi, K. et al, Bi ochem. Biophys. Res. Commun. 244 (1) , 268 - 274 (1998)  Na, K-ATPase subunit alpha 2 (ATP1A2) / 34377-at / J05096 / NM_000702 / P_000693 / Shull, MM et al, J. Biol. Chem. 264 (29), 17532-17543 (1989) aquaporin 9/34435 — At / AB008775 / Orchid — 020980 / NP— 066190 / Ishibashi, K. et al, Biochem. Biophys. Res. Commun. 244 (1), 268-274 (1998)
pleiotrophin /34820一 at /M57399 /NM— 002825 /NP一 002816 /Tezuka, K. et al, Bi ochem. Biophys. Res. Commun. 173 (1)， 246-251 (1990) pleiotrophin / 34820 at / M57399 / NM— 002825 / NP-002816 / Tezuka, K. et al, Biochem. Biophys. Res. Commun. 173 (1), 246-251 (1990)
cadherin 19, type 2 /34922_at /AF047826 /NM— 021153 /NP— 066976 /Kools, P. et al, Genomics 68 (3) , 283-295 (2000) cadherin 19, type 2 / 34922_at / AF047826 / NM— 021153 / NP— 066976 / Kools, P. et al, Genomics 68 (3), 283-295 (2000)
WNT inhibitory factor 1 /35178_at /W27944 /NM— 007191 /NP— 009122 /Hsieh, J. C. et al, Nature 398 (6726)， 431-436 (1999) WNT inhibitory factor 1 / 35178_at / W27944 / NM— 007191 / NP— 009122 / Hsieh, J.C. et al, Nature 398 (6726), 431-436 (1999)
reversion - inducing - cysteine- rich protein with kazal motifs /35234—at /D 50406 /NM— 021111 /NP— 066934 /Takahashi, C. et al, Proc. Natl. Acad. Sci. U. S. A. 95 (22) , 13221-13226 (1998) reversion-inducing-cysteine-rich protein with kazal motifs / 35234—at / D 50406 / NM— 021111 / NP—066934 / Takahashi, C. et al, Proc. Natl. Acad. Sci. USA 95 (22), 13221- 13226 (1998)
insulin induced gene 1 /35303— at /U96876 /NM— 005542 /NP— 005533 /Peng, Y. et al, Genomics 43 (3) , 278-284 (1997) insulin induced gene 1 / 35303— at / U96876 / NM— 005542 / NP— 005533 / Peng, Y. et al, Genomics 43 (3), 278-284 (1997)
11-beta-hydroxysteroid dehydrogenase (HSD11) /35702— at /M76665 /NM—0055 25 /NP一 005516 /Tannin, G. M. et al, J. Biol. Chem. 266 (25) , 16653-16658 (1991) 11-beta-hydroxysteroid dehydrogenase (HSD11) / 35702—at / M76665 / NM—0055 25 / NP-005516 / Tannin, GM et al, J. Biol. Chem. 266 (25), 16653-16658 (1991)
myelin basic protein /35817一 at /M13577 /NM— 002385 /NP— 002376 /Kamholz J. et al， Proc. Natl. Acad. Sci. U. S. A. 83 (13) , 4962 - 4966 (1986) galanin /35879_at / 77140 /- /AAA60178 /McKnight, G. L et al, Diabetes 41 (1)， 82-87 (1992) myelin basic protein / 35817 at / M13577 / NM— 002385 / NP— 002376 / Kamholz J. et al, Proc. Natl. Acad. Sci. USA 83 (13), 4962-4966 (1986) galanin / 35879_at / 77140 / -/ AAA60178 / McKnight, G. L et al, Diabetes 41 (1), 82-87 (1992)
W T1 inducible signaling pathway protein 2 (WISP2) /35898_at /AF100780 /NM一 003881 /NP一 003872 /Pennica, D. et al, Proc. Natl. Acad. Sci. U. S. A. W T1 inducible signaling pathway protein 2 (WISP2) / 35898_at / AF100780 / NM-003881 / NP-003872 / Pennica, D. et al, Proc. Natl. Acad. Sci. U.S.A.
95 (25)， 14717-14722 (1998) 95 (25), 14717-14722 (1998)
LIM domain binding 2 I CLIM1 /36065_at /AF052389 /NM— 001290ノ NP_001281 /Semina, E. V. et al, Ma讓. Genome 9 (11) , 921-924 (1998) LIM domain binding 2 I CLIM1 / 36065_at / AF052389 / NM— 001290 NP_001281 / Semina, E.V. et al, Ma Sub. Genome 9 (11), 921-924 (1998)
dihydropyrimidinase-like 3 /36149— at /D78014 /NM_0O1387 /NP— 001378 /Ham ajima, N. et al, Gene 180 (1-2) , 157-163 (1996) dihydropyrimidinase-like 3 / 36149— at / D78014 / NM_0O1387 / NP— 001378 / Ham ajima, N. et al, Gene 180 (1-2), 157-163 (1996)
ATPase, Ca++ transporting, ubiquitous /36482_s_at /Y15724 /NM— 005173 /N P一 005164 /Dode, L. et al, Biochem. J. 318 (Pt 2) , 689-699 (1996) glypican 4 /36508— at /AF030186 /NM_001448 /NP— 001439 /Veugelers, M. et a 1， Genomics 53 (1) , 1—11 (1998)  ATPase, Ca ++ transporting, ubiquitous / 36482_s_at / Y15724 / NM- 005173 / NP-005164 / Dode, L. et al, Biochem. J. 318 (Pt 2), 689-699 (1996) glypican 4 / 36508— at / AF030186 / NM_001448 / NP— 001439 / Veugelers, M. et a 1, Genomics 53 (1), 1—11 (1998)
acetylserotonin 0-methyltransf erase-1 ike /36554_at /Y15521 /NM— 004192 / NP一 004183 /Ried, K. et al, Hum. Mol. Genet. 7 (11) , 1771 - 1778 (1998) synuclein, gamma /36555_at /AF044311 / I_003087 /NP一 003078 /Ji, H. et al,acetylserotonin 0-methyltransf erase-1 ike / 36554_at / Y15521 / NM— 004192 / NP-004183 / Ried, K. et al, Hum.Mol. Genet. 7 (11), 1771-1778 (1998) synuclein, gamma / 36555_at / AF044311 / I_003087 / NP-003078 / Ji, H. et al,
Cancer Res. 57 (4)， 759-764 (1997) Cancer Res. 57 (4), 759-764 (1997)
connective tissue growth factor /36638_at /X78947 /NM— 001901 /NP— 001892 /Oemar, B. S. et al, Circulation 95 (4)， 831-839 (1997) connective tissue growth factor / 36638_at / X78947 / NM— 001901 / NP— 001892 / Oemar, B.S. et al, Circulation 95 (4), 831-839 (1997)
tropomyosin 1 (alpha) /36791_g_at /M19267 /NM— 000366 /NP— 000357 /Lin, C. S. et al, Mol. Cell. Biol. 8 (1)， 160-168 (1988) tropomyosin 1 (alpha) / 36791_g_at / M19267 / NM—000366 / NP—000357 / Lin, C.S.et al, Mol.Cell.Biol. 8 (1), 160-168 (1988)
breast cancer anti-estrogen resistance 3 /36812_at /U92715 /NM—003567 I NP一 003558 /van Agthoven, T. et al, EMB0 J. 17 (10) , 2799-2808 (1998) heat shock 70kDa protein 2 /36925_at /L26336 /NM一 021979 /NP— 068814 /Bon nycastle, L. L. et al, Genomics 23 (1) , 85 - 93 (1994) breast cancer anti-estrogen resistance 3 / 36812_at / U92715 / NM-003567 INP-003558 / van Agthoven, T. et al, EMB0 J. 17 (10), 2799-2808 (1998) heat shock 70kDa protein 2 / 36925_at / L26336 / NM-I 21979 / NP- 068814 / Bon nycastle, LL et al, Genomics 23 (1), 85-93 (1994)
ets variant gene 1 /37156_at /AF070641 /NM一 004956 /NP一 004947 /Jeon, I. S. et al, Oncogene 10 (6) , 1229-1234 (1995) ets variant gene 1 / 37156_at / AF070641 / NM-004956 / NP-004947 / Jeon, I.S. et al, Oncogene 10 (6), 1229-1234 (1995)
protein kinase, cA P - dependent, regulatory, type II， beta /37221— at /M3 1158 /NM— 002736 /NP一 002727 /Levy, F. 0. et al, Mol. Endocrinol. 2 (12) , 1 364-1373 (1988) protein kinase, cA P-dependent, regulatory, type II, beta / 37221— at / M3 1158 / NM— 002736 / NP-002727 / Levy, F. 0. et al, Mol. Endocrinol. 2 (12), 1 364 -1373 (1988)
microtubule - associated protein, RP/EB family, member 2 /37406一 at /X9423 2 /N一 014268 /NP一 055083 /Renner, C. et al, J. Immunol. 159 (3)， 1276-12 83 (1997) microtubule-associated protein, RP / EB family, member 2 / 37406-at / X94232 / N-014268 / NP055083 / Renner, C. et al, J. Immunol. 159 (3), 1276-1283 (1997 )
ATP - binding cassette, sub-family C (CFTR/MRP) , member 3 isoform MRP3A / 38261— at /AF085691 / L020037 /NP— 064421 /Fromra, M. F. et al, Biochim. B iophys. Acta 1415 (2)， 369 - 374 (1999)  ATP-binding cassette, sub-family C (CFTR / MRP), member 3 isoform MRP3A / 38261— at / AF085691 / L020037 / NP— 064421 / Fromra, MF et al, Biochim. Biophys. Acta 1415 (2), 369 -374 (1999)
ATP- binding cassette, sub-family C (CFTR/MRP) , member 3 isoform MRP3B / 38261— at /AF085692 /NM— 020038 /NP— 064422 /Froram, M. F. et al, Biochim. Bi ophys. Acta 1415 (2) , 369-374 (1999)  ATP-binding cassette, sub-family C (CFTR / MRP), member 3 isoform MRP3B / 38261—at / AF085692 / NM—020038 / NP—064422 / Froram, MF et al, Biochim. Bi ophys. Acta 1415 (2) , 369-374 (1999)
transmembrane 4 superfamily member 2 /38408— at /L10373 /應— 004615 /NP— 0transmembrane 4 superfamily member 2 / 38408—at / L10373 / O—004615 / NP—0
04606 /Takagi, S. et al, Int. J. Cancer 61 (5) , 706—715 (1995) 04606 / Takagi, S. et al, Int.J. Cancer 61 (5), 706—715 (1995)
AXL receptor tyrosine kinase isoform 1 /38433_at /S65125 /NM一 021913 /NP AXL receptor tyrosine kinase isoform 1 / 38433_at / S65125 / NM-1 021913 / NP
—068713 /Janssen, J. W. et al, Oncogene 6 (11) , 2113-2120 (1991) —068713 / Janssen, J.W. et al, Oncogene 6 (11), 2113-2120 (1991)
AXL receptor tyrosine kinase isoform 2 /38433_at /M76125 /NM— 001699 /NP AXL receptor tyrosine kinase isoform 2 / 38433_at / M76125 / NM— 001699 / NP
—001690 /- phospholamban /38734_at /M63603 /NM— 002667 /NP— 002658 /Fujii, J. et al,—001690 /-phospholamban / 38734_at / M63603 / NM— 002667 / NP— 002658 / Fujii, J. et al,
J. Biol. Chem. 266 (18) , 11669-11675 (1991) J. Biol. Chem. 266 (18), 11669-11675 (1991)
Fc fragment of IgG binding protein /39014_at /D84239 /匪— 003890 /NP_003 881 /Harada, N. , J. Biol. Chem. 272 (24) , 15232 - 15241 (1997) microsomal glutathione S - transferase 3 /39018— at /AF026977 / — 004528 / NP一 004519 /Jakobsson, P. J. et al, J. Biol. Chem. 272 (36)， 22934-22939 (1997) Fc fragment of IgG binding protein / 39014_at / D84239 / marauder 003890 / NP_003 881 / Harada, N., J. Biol. Chem. 272 (24), 15232-15241 (1997) microsomal glutathione S-transferase 3 / 39018— at / AF026977 / — 004528 / NP-004519 / Jakobsson, PJ et al, J. Biol. Chem. 272 (36), 22934-22939 (1997)
cytochrome c oxidase subunit Vila polypeptide 1 (muscle) /39031— at /Ml 52406 /NM_001864 /NP一 001855 /Arnaudo, E. et al, Gene 119 (2) , 299-305 (1992) cytochrome c oxidase subunit Vila polypeptide 1 (muscle) / 39031— at / Ml 52406 / NM_001864 / NP-001855 / Arnaudo, E. et al, Gene 119 (2), 299-305 (1992)
DEPP (decidual protein induced by progesterone) /39114一 at /AB022718 /NM 一 007021 / P_008952 /- myosin, light polypeptide 9, regulatory /39145一 at /J02854 /NM— 006097 /N DEPP (decidual protein induced by progesterone) / 39114 at / AB022718 / NM 007021 / P_008952 /-myosin, light polypeptide 9, regulatory / 39145 at at / J02854 / NM— 006097 / N
P一 006088 /Kumar, C. C. et al, Biochemistry 28 (9) , 4027-4035 (1989)P-006088 / Kumar, C.C. et al, Biochemistry 28 (9), 4027-4035 (1989)
Arg/Abl-interacting protein ArgBP2a /39295_s_at /AF049884 /NM— 003603 /NArg / Abl-interacting protein ArgBP2a / 39295_s_at / AF049884 / NM— 003603 / N
P一 003594 /Wang, B. et al, J. Biol. Chem. 272 (28)， 17542-17550 (1997)P-003594 / Wang, B. et al, J. Biol. Chem. 272 (28), 17542-17550 (1997)
Arg/Abl-interacting protein ArgBP2b /39295— s— at /AB018320 /NM— 021069 /NArg / Abl-interacting protein ArgBP2b / 39295—s—at / AB018320 / NM—021069 / N
P一 066547 /Nagase, T. et al, DNA Res. 5 (5)， 277—286 (1998) P-1 066547 / Nagase, T. et al, DNA Res. 5 (5), 277-286 (1998)
fatty acid desaturase 1 /39372_at /W26480 /NM— 013402 /NP— 037534 /Leonar d, A. E. et al, Biochem. J. 347 Pt 3, 719—724 (2000) fatty acid desaturase 1 / 39372_at / W26480 / NM— 013402 / NP— 037534 / Leonard, A. E. et al, Biochem. J. 347 Pt 3, 719—724 (2000)
homeo box B2 /39610— at /XI 6665 /NM— 002145 /NP— 002136 /- frizzled- related protein /40230— at /U91903 /NM— 001463 /NP— 001454 /Hoang,homeo box B2 / 39610— at / XI 6665 / NM— 002145 / NP— 002136 /-frizzled- related protein / 40230— at / U91903 / NM— 001463 / NP— 001454 / Hoang,
B. et al, J. Biol. Chem. 271 (42) , 26131—26137 (1996) B. et al, J. Biol. Chem. 271 (42), 26131-26137 (1996).
G protein-coupled receptor, family C, group 5, member B /40240_at /AC00 G protein-coupled receptor, family C, group 5, member B / 40240_at / AC00
4131 /NM一 016235 /NP— 057319 /Robbins, . J. et al, Genomics 67 (1)， 8-184131 / NM-016235 / NP— 057319 / Robbins,. J. et al, Genomics 67 (1), 8-18
(2000) (2000)
GABA-A receptor pi subunit /40339— at /U95367 /丽— 014211 /NP_055026 /He dblom, E. et al, J. Biol. Chem. 272 (24) , 15346-15350 (1997)  GABA-A receptor pi subunit / 40339— at / U95367 / 丽 — 014211 / NP_055026 / He dblom, E. et al, J. Biol. Chem. 272 (24), 15346-15350 (1997)
mesenchyme homeo box 2 /40398— s— at /AI743406 /腿— 005924 /NP—005915 /Gri goriou, M. et al, Genomics 26 (3)， 550 - 555 (1995) KIAA1053 protein /40855_at /AB028976 /NM_015589 /NP— 056404 /- KIAA0729 protein /41219— at /AL050376 /- /- /- keratin 7 /41294— at /AJ238246 /NM一 005556 /NP— 005547 /Glass, C. et al,mesenchyme homeo box 2 / 40398—s—at / AI743406 / thigh—005924 / NP—005915 / Gri goriou, M. et al, Genomics 26 (3), 550-555 (1995) KIAA1053 protein / 40855_at / AB028976 / NM_015589 / NP— 056404 /-KIAA0729 protein / 41219—at / AL050376 /-/-/-keratin 7 / 41294—at / AJ238246 / NM- 005556 / NP—005547 / Glass, C. et al,
J. Cell Biol. 107 (4) , 1337-1350 (1988) J. Cell Biol. 107 (4), 1337-1350 (1988)
KIAA1467 protein /41826— at /W28287 /AB040900 /- /- tumor-associated calcium signal transducer 1 /575_s_at /M93036 /NM一 0023 54 /NP一 002345 /Strnad, J. et al, Cancer Res. 49 (2) , 314-317 (1989) CYPIBI /859_at /U03688 /NM— 000104 /NP— 000095 /Sutter, T. R. et al, J. Bi ol. Chem. 269 (18) , 13092-13099 (1994)  KIAA1467 protein / 41826-- at / W28287 / AB040900 /-/-tumor-associated calcium signal transducer 1 / 575_s_at / M93036 / NM-002354 / NP-002345 / Strnad, J. et al, Cancer Res. 49 (2), 314-317 (1989) CYPIBI / 859_at / U03688 / NM—000104 / NP—000095 / Sutter, TR et al, J. Biol. Chem. 269 (18), 13092-13099 (1994)
interleukin 1 receptor, type II /998一 s一 at /X59770 /NM— 004633 /NP— 004624 /McMahan, C. J. et al, EMBO J. 10 (10) , 2821-2832 (1991) interleukin 1 receptor, type II / 998-1 s-1 at / X59770 / NM- 004633 / NP- 004624 / McMahan, C. J. et al, EMBO J. 10 (10), 2821-2832 (1991)
platelet/endothelial cell adhesion molecule (CD31) /268一 at /L34657 /NM一 000442 /NP一 000433 /Newman, P. J. et al, Science 247 (4947) , 1219—1222 (1 990) platelet / endothelial cell adhesion molecule (CD31) / 268-at / L34657 / NM-000442 / NP-000433 / Newman, P.J. et al, Science 247 (4947), 1219-1222 (1 990)
act in, alpha 2， smooth muscle, aorta /32755_at /X13839 /NM— 001613 /NP_0act in, alpha 2, smooth muscle, aorta / 32755_at / X13839 / NM— 001613 / NP_0
01604 /Kamada, S. et al, Nucleic Acids Res. 17 (4) , 1767 (1989) 01604 / Kamada, S. et al, Nucleic Acids Res. 17 (4), 1767 (1989)
GRB2 - associated binding protein 2 isoform a /35253一 at /AB018413 /Ml一 080 GRB2-associated binding protein 2 isoform a / 35 253 at / AB018413 / Ml 080
491 /NP一 536739 /Nishida, K. et al, Blood 93 (6) , 1809-1816 (1999)491 / NP-1 536739 / Nishida, K. et al, Blood 93 (6), 1809-1816 (1999)
GRB2— associated binding protein 2 isoform b /35253_at /AB011143 /NM一 012GRB2—associated binding protein 2 isoform b / 35253_at / AB011143 / NM-012
296 /NP_036428 /— 296 / NP_036428 / —
DKFZp586I1823 /36092— at /AL080213 /一 /- /一  DKFZp586I1823 / 36092—at / AL080213 / one /-/ one
mitogen inducible 2 /36577_at /Z24725 /Z24725 /CAA80852 /Wick, M. et al,mitogen inducible 2 / 36577_at / Z24725 / Z24725 / CAA80852 / Wick, M. et al,
J. Cell. Sci. 107 (Pt 1) , 227-239 (1994) J. Cell. Sci. 107 (Pt 1), 227-239 (1994)
KIAA0280 /36612— at /D87470 /D87470 /BAA13408 /- transgelin /36931_at /M95787 /丽一 003186 /NP— 003177 /Thweatt, R. et al, B iochem. Biophys. Res. Commun. 187 (1)， 1-7 (1992) deleted in liver cancer 1 /37951— at /AF035119 / — 006094 / P_006085 /Y uan' B. Z. et al, Cancer Res. 58 (10) , 2196-2199 (1998) KIAA0280 / 36612—at / D87470 / D87470 / BAA13408 / -transgelin / 36931_at / M95787 / 丽 -003186 / NP—003177 / Thweatt, R. et al, Biochem. Biophys. Res. Commun. 187 (1), 1- 7 (1992) deleted in liver cancer 1 / 37951— at / AF035119 / — 006094 / P_006085 / Yuan 'BZ et al, Cancer Res. 58 (10), 2196-2199 (1998)
DKFZp5640222 /38312_at /AL050002 /AL050002 /一 /一 DKFZp5640222 / 38312_at / AL050002 / AL050002 / one / one
8-oxoguanine DNA glycosylase isoform 2a /38335_at /U88620細— 016821 /N P— 058214 /Aburatani, H. et al, Cancer Res. 57 (11)， 2151-2156 (1997) 8-oxoguanine DNA glycosylase isoform 2b /38335_at /AB019528 /NM— 016826 /NP一 058434 /Nishioka, K et al, Mol. Biol. Cell 10 (5) , 1637—1652 (1999) 8-oxoguanine DNA glycosylase isoform 2c /38335_at /AB019529 /NM一 016827 /NP一 058436 /Nishioka, K et al, Mol. Biol. Cell 10 (5)， 1637—1652 (1999) 8-oxoguanine DNA glycosylase isoform 2d /38335_at /AB019530 /NM一 016828 /NP_058437 /Nishioka, K et al, Mol. Biol. Cell 10 (5) , 1637-1652 (1999) 8-oxoguanine DNA glycosylase isoform 2e /38335_at /ABO 19531 /NM_016829 /NP一 058438 /Nishioka, et al, Mol. Biol. Cell 10 (5)， 1637-1652 (1999) enolase 2, (gamma, neuronal) /40193— at /X51956 /NM— 001975 /NP— 001966 /0 liva, D. et al, Genomics 10 (1) , 157-165 (1991)  8-oxoguanine DNA glycosylase isoform 2a / 38335_at / U88620 Fine 016821 / NP-058214 / Aburatani, H. et al, Cancer Res. 57 (11), 2151-2156 (1997) 8-oxoguanine DNA glycosylase isoform 2b / 38335_at / AB019528 / NM— 016826 / NP-058434 / Nishioka, K et al, Mol.Biol.Cell 10 (5), 1637—1652 (1999) 8-oxoguanine DNA glycosylase isoform 2c / 38335_at / AB019529 / NM-016827 / NP-1 058436 / Nishioka, K et al, Mol.Biol. Cell 10 (5), 1637-1652 (1999) 8-oxoguanine DNA glycosylase isoform 2d / 38335_at / AB019530 / NM-016828 / NP_058437 / Nishioka, K et al, Mol. Biol. Cell 10 (5), 1637-1652 (1999) 8-oxoguanine DNA glycosylase isoform 2e / 38335_at / ABO 19531 / NM_016829 / NP-1 058438 / Nishioka, et al, Mol. Biol. Cell 10 (5), 1637- 1652 (1999) enolase 2, (gamma, neuronal) / 40193— at / X51956 / NM— 001975 / NP— 001966/0 liva, D. et al, Genomics 10 (1), 157-165 (1991)
pinin, desmosorae associated protein /41574—at /Y09703 /NM— 002687 /NP一 00 2678 /Ouyang, P. et al, J. Cell Biol. 135 (4) , 1027-1042 (1996) pinin, desmosorae associated protein / 41574-at / Y09703 / NM- 002687 / NP-00 2678 / Ouyang, P. et al, J. Cell Biol. 135 (4), 1027-1042 (1996)
KIAA0716 /41620— at /AB018259 /NM— 014705 /NP— 055520 /- 一データ 1 1 ： KIAA0716 / 41620— at / AB018259 / NM— 014705 / NP— 055520 /-One data 1 1:
(ァトピー性皮膚炎と乾癬患者の皮膚組織における遺伝子努現を健常者皮膚組 織と比較した結果、 乾癬患者の無疹部でのみ発現変動 Z上昇が認められた遺伝 子）  (Comparison of genetic efforts in skin tissues of patients with atopic dermatitis and psoriasis and a gene whose expression fluctuation Z was increased only in the eruption of psoriatic patients as a result of comparison with skin tissues of healthy subjects)
platelet factor 4 (PF4) I 1115_at / M25897 / NM一 002619 / NP— 002610 I Po ncz' M. et al, Blood 69 (1)， 219 - 223 (1987) platelet factor 4 (PF4) I 1115_at / M25897 / NM-002619 / NP— 002610 I Po ncz 'M. et al, Blood 69 (1), 219-223 (1987)
actin, gamma 2, smooth muscle, enteric / 1197一 at I D00654 /腿一 001615 / NP— 001606 / Miwa, T. et al, Nucleic Acids Res. 18 (14) , 4263 (1990) interferon (alpha, beta and omega) receptor 2 I 1589_s_at / L42243 / NM —000874 I NP一 000865 / Novick, D. et al, Cell 77 (3) , 391-400 (1994) DM topoisomerase I / 1710一 s一 at I U07804 / NM_003286 / NP_003277 / D' Ar pa, P. et al, Proc. Natl. Acad. Sci. U. S. A. 85 (8) , 2543-2547 (1988) CYP3A4 I 1756一 f— at / D00003 / NM— 000776 / NP_000767 / Molowa, D. T. et al,actin, gamma 2, smooth muscle, enteric / 1197-1 at I D00654 / Thigh 001615 / NP- 001606 / Miwa, T. et al, Nucleic Acids Res. 18 (14), 4263 (1990) interferon (alpha, beta and omega) receptor 2 I 1589_s_at / L42243 / NM -000874 I NP-000865 / Novick, D. et al, Cell 77 (3), 391-400 (1994) DM topoisomerase I / 1710-1 s-1 at I U07804 / NM_003286 / NP_003277 / D 'Ar pa, P. et al, Proc. Natl. Acad. Sci. USA 85 (8), 2543-2547 (1988) CYP3A4 I 1756 f-at / D00003 / NM- 000776 / NP_000767 / Molowa, DT et al,
Proc. Natl. Acad. Sci. U. S. A. 83 (14) , 5311-5315 (1986) Proc. Natl. Acad. Sci. U.S.A. 83 (14), 5311-5315 (1986)
cyclin - dependent kinase 2 isoform 1 / 1833一 at / M68520 / NM— 001798 I NP —001789 I Tsai, L. H. et al, Nature 353 (6340) , 174 - 177 (1991) cyclin-dependent kinase 2 isoform 1/1833 at / M68520 / NM— 001798 I NP —001789 I Tsai, L. H. et al, Nature 353 (6340), 174-177 (1991)
cyclin - dependent kinase 2 isoform 2 / 1833— at / ABO 12305 / NM— 052827 / NP— 439892 / Tsai, L. H. et al, Nature 353 (6340) , 174-177 (1991) cyclin-dependent kinase 2 isoform 2/1833-at / ABO 12305 / NM-052827 / NP-439892 / Tsai, L. H. et al, Nature 353 (6340), 174-177 (1991)
vascular endothelial growth factor - D I 1958— at / AJ000185 / NM— 004469 /vascular endothelial growth factor-D I 1958— at / AJ000185 / NM— 004469 /
NP— 004460 I Yamada, Y. et al, Genomics 42 (3)， 483-488 (1997) NP— 004460 I Yamada, Y. et al, Genomics 42 (3), 483-488 (1997)
ABLl isoform a / 2041— i一 at I Ml 4752 / NM— 005157 / NP_005148 / Shtivelma n，E. et al, Cell 7 (2) , 277—284 (1986) ABLl isoform a / 2041-i-I at I Ml 4752 / NM-005157 / NP_005148 / Shtivelman, E. et al, Cell 7 (2), 277-284 (1986)
ABLl isoform b / 2041— i— at / M14752 / NM— 007313 / NP一 009297 / Shtivelma n, E. et al, Cell 47 (2) , 277—284 (1986)  ABLl isoform b / 2041—i—at / M14752 / NM—007313 / NP-1 009297 / Shtivelman, E. et al, Cell 47 (2), 277—284 (1986)
adducin 1 (alpha) isoform c / 32146— s— at / L07261 / NM— 014190 / NP— 0549 09 I Joshi, R. et al, J. Cell Biol. 115 (3) , 665 - 675 (1991) adducin 1 (alpha) isoform c / 32146-s-at / L07261 / NM-014190 / NP-0549 09 I Joshi, R. et al, J. Cell Biol. 115 (3), 665-675 (1991)
KLRC3 isoform NKG2-E I 32287— s— at / AJ001685 / NM一 002261 / NP— 002252 I Adamkiewicz, T. V. et al, Immunogenetics 39 (3) , 218 (1994) KLRC3 isoform NKG2-E I 32287—s—at / AJ001685 / NM-002261 / NP—002252 I Adamkiewicz, T.V. et al, Immunogenetics 39 (3), 218 (1994)
KLRC3 isoform KG2-H / 32287一 s— at / AJ001685 / NM— 007333 / NP— 031359 I Bellon, T. et al, J. Immunol. 162 (7)， 3996-4002 (1999) KLRC3 isoform KG2-H / 32287-s-at / AJ001685 / NM-007333 / NP-03031359 I Bellon, T. et al, J. Immunol. 162 (7), 3996-4002 (1999)
RAB2 I 32581— at / AF070629 / 丽— 002865 / NP— 002856 / Tachibana, K. et al, Nucleic Acids Res. 16 (21) , 10368 (1988) RAB2 I 32581—at / AF070629 / 丽 —002865 / NP—002856 / Tachibana, K. et al, Nucleic Acids Res. 16 (21), 10368 (1988)
1 acylglyceroト 3 - phosphate 0-acyltransf erase 2 I 32837一 at / U56418 I 匪 一 006412 I NP_006403 / West J. et al, DNA Cell Biol. 16 (6) , 691—701 (19 97) 1 acylglycero to 3-phosphate 0-acyltransf erase 2 I 32837 at / U56418 I Martian 006412 I NP_006403 / West J. et al, DNA Cell Biol. 16 (6), 691—701 (19 97)
tryptase, alpha / 32905_s_at / M30038 / NM_003293 / NP_003284 / Miller, J. S. et al, J. Clin. Invest. 84 (4)， 1188 - 1195 (1989) tryptase, alpha / 32905_s_at / M30038 / NM_003293 / NP_003284 / Miller, J.S. et al, J. Clin. Invest. 84 (4), 1188-1195 (1989)
homolog of Yeast RRP4 I 32975_g_at / U07563 / NM一 014285 / NP_055100 /一 MCM3 I 33252— at / D38073 / NM— 002388 / NP一 002379 / Tho脆 es， P. et al, Nu oleic Acids Res. 20 (5)， 1069-1074 (1992) homolog of Yeast RRP4 I 32975_g_at / U07563 / NM-1014285 / NP_055100 / -1 MCM3 I 33252— at / D38073 / NM— 002388 / NP-1 002379 / Tho brittle es, P. et al, Nuoleic Acids Res. 20 (5) , 1069-1074 (1992)
hemoglobin, delta / 33516一 at / V00505 / NM一 000519 / NP— 000510 / Lawn, R.hemoglobin, delta / 335516 at / V00505 / NM 000519 / NP— 000510 / Lawn, R.
M. et al, Cell 15 (4)， 1157-1174 (1978) M. et al, Cell 15 (4), 1157-1174 (1978)
KIAA1089 I 34868— at / AB029012 I NM一 015327 / NP—056142 / - zinc finger protein 44 (KOX 7) / 35409_r_at / X16281 I - I - I - arylacetamide deacetylase (esterase) / 36512_at / L32179 / NM— 001086 / KIAA1089 I 34868— at / AB029012 I NM-015327 / NP-056142 /-zinc finger protein 44 (KOX 7) / 35409_r_at / X16281 I-I-I-arylacetamide deacetylase (esterase) / 36512_at / L32179 / NM— 001086 /
NP一 001077 I Probst, M. R. et al, J. Biol. Chem. 34, 21650-21656 (1994) synuclein, gamma / 36555— at / AF044311 / NM一 003087 / NP— 003078 / Ji, H. et al, Cancer Res. 57 (4) , 759-764 (1997) NP-001077 I Probst, MR et al, J. Biol. Chem. 34, 21650-21656 (1994) synuclein, gamma / 36555—at / AF044311 / NM-003087 / NP—003078 / Ji, H. et al, Cancer Res. 57 (4), 759-764 (1997)
elastase 2, neutrophil / 37096一 at / M34379 / NM一 001972 / NP一 001963 I 0k ano K. et al, J. Biochem. 102 (1)， 13-16 (1.987) elastase 2, neutrophil / 37096 at / M34379 / NM 001972 / NP 001963 I 0k ano K. et al, J. Biochem. 102 (1), 13-16 (1.987)
CYP3A5 I 37124— i— at / J04813 / NM— 000777 / NP—000768 / Aoyama, T. et al, CYP3A5 I 37124—i—at / J04813 / NM—000777 / NP—000768 / Aoyama, T. et al,
J. Biol. Chem. 264 (18)， 10388-10395 (1989) J. Biol. Chem. 264 (18), 10388-10395 (1989)
FCGR3A (CD16) / 37200_at / J04162 / NM— 000569 / NP一 000560 / Peltz, G. A. et al, Proc. Natl. Acad. Sci. U. S. A. 86 (3)， 1013 - 1017 (1989) FCGR3A (CD16) / 37200_at / J04162 / NM—000569 / NP-000560 / Peltz, G.A. et al, Proc. Natl. Acad. Sci. U.S.A. 86 (3), 1013-1017 (1989)
likely ortholog of mouse neural in 1 / 37630— at / AL049176 / NM— 145234 /likely ortholog of mouse neural in 1 / 37630— at / AL049176 / NM— 145234 /
NP_660277 / Cof f inier, C. et al, Mech. Dev. 100 (1) , 119-122 (2001) pyruvate carboxylase / 38000— at / S72370 / NM_000920 / NP— 000911 I Frey tag, S. 0. et al, J. Biol. Chem. 259 (20)， 12831—12837 (1984) NP_660277 / Cof finier, C. et al, Mech. Dev. 100 (1), 119-122 (2001) pyruvate carboxylase / 38000— at / S72370 / NM_000920 / NP— 000911 I Frey tag, S. 0. et al , J. Biol. Chem. 259 (20), 12831-12837 (1984).
2' , 5' -oligoadenylate synthetase 1 isoforra E16 I 38388— at / X04371 I NM一 002534 I NP一 002525 / Saunders, M. E. et al, EMBO J. 4 (9) , 2249-2256 (198 5) 2 ', 5' -oligoadenylate synthetase 1 isoforra E16 I 38388- at / X04371 I NM-002534 I NP-002525 / Saunders, ME et al, EMBO J. 4 (9), 2249-2256 (198 Five)
2，， 5' -oligoadenylate synthetase 1 isoform E18 / 38388一 at / X02875 / NM一 016816 / NP— 058132 / Saunders, . E. et al, EMBO J. 4 (9) , 2249-2256 (198 5)  2 ,, 5'-oligoadenylate synthetase 1 isoform E18 / 38388 at / X02875 / NM-016816 / NP— 058132 / Saunders, .E. Et al, EMBO J. 4 (9), 2249-2256 (198 5)
muscle RAS oncogene homolog / 38540— at / AF043938 / NM— 012219 / NP— 0363 51 I - butyrophilin, subfamily 3， member A2 I 38760— f— at / U90546 I NM一 007047muscle RAS oncogene homolog / 38540— at / AF043938 / NM— 012219 / NP— 0363 51 I-butyrophilin, subfamily 3, member A2 I 38760— f—at / U90546 I NM-007070
/ NP一 008978 I Ruddy DA et al, Genome Res. 7 (5)， 441-456 (1997) / NP-008989 I Ruddy DA et al, Genome Res. 7 (5), 441-456 (1997)
CXCL7 I 39208_i_at / M54995 I 丽ー 002704 / NP— 002695 / Wenger, R. H. et al, CXCL7 I 39208_i_at / M54995 I page 002704 / NP— 002695 / Wenger, R. H. et al,
Blood 73 (6) , 1498-1503 (1989) Blood 73 (6), 1498-1503 (1989)
Arg Abl - interacting protein ArgBP2a / 39295— s— at / AF049884 I NM_003603Arg Abl-interacting protein ArgBP2a / 39295—s—at / AF049884 I NM_003603
I NP一 003594 / Wang, B. et al, J. Biol. Chem. 272 (28) , 17542—17550 (199 7) I NP- 003594 / Wang, B. et al, J. Biol. Chem. 272 (28), 17542-17550 (199 7)
Arg Abl- interacting protein ArgBP2b / 39295— s— at / AB018320 / NM— 021069 Arg Abl- interacting protein ArgBP2b / 39295—s—at / AB018320 / NM—021069
I NP一 066547 / Nagase, T. et al, DNA Res. 5 (5) , 277-286 (1998) I NP-1 066547 / Nagase, T. et al, DNA Res. 5 (5), 277-286 (1998)
FLJ33034 I 39296— at / W28319 I - I - I - calpain 3 / 39301— at / X85030 / NM— 000070 / NP— 000061 / Richard, I. et a 1， Cell 81 (1)， 27-40 (1995) FLJ33034 I 39296— at / W28319 I-I-I-calpain 3/39301 — at / X85030 / NM — 000070 / NP — 000061 / Richard, I. et a 1, Cell 81 (1), 27-40 (1995)
bleomycin hydrolase / 394_at / X92106 / NM— 000386 / NP— 000377 I Ferrandbleomycin hydrolase / 394_at / X92106 / NM— 000386 / NP— 000377 I Ferrand
0, A. A. et al, Cancer Res. 56 (8)， 1746-1750 (1996) 0, A. A. et al, Cancer Res. 56 (8), 1746-1750 (1996)
desmuslin isoform A I 39544— at / AJ310522 / NM— 145728 I NP— 663780 I - desmuslin isoform B I 39544— at / AJ310521 / NM— 015286 / NP— 056101 I - TAF6L / 39908— at / AF069735 I 丽— 006473 / NP— 006464 / Ogryzko, V. V. et adesmuslin isoform AI 39544— at / AJ310522 / NM— 145728 I NP— 663780 I-desmuslin isoform BI 39544— at / AJ310521 / NM— 015286 / NP— 056101 I-TAF6L / 39908— at / AF069735 I 丽 — 006473 / NP— 006464 / Ogryzko, VV et a
1, Cell 94 (1) , 35-44 (1998) 1, Cell 94 (1), 35-44 (1998)
ESTs / 40428_i_at I AW043812 I - I - I - ESTs / 40428_i_at I AW043812 I-I-I-
FLJ22269 / 40772— at I 284298 I NM一 032219 / NP_115595 / - keratin 7 / 41294— at / AJ238246 / NM— 005556 / NP_005547 / Glass, C. et a 1, J. Cell Biol. 107 (4) , 1337-1350 (1988) FLJ22269 / 40772—at I 284298 I NM 032219 / NP_115595 /- keratin 7 / 41294—at / AJ238246 / NM—005556 / NP_005547 / Glass, C. et a 1, J. Cell Biol. 107 (4), 1337-1350 (1988)
scaffold attachment factor B / 41315一 at / AA456343 / NM— 002967 / NP_002 958 I Renz, A. et al, Nucleic Acids Res. 24 (5) , 843-849 (1996) scaffold attachment factor B / 41315 at / AA456343 / NM— 002967 / NP_002 958 I Renz, A. et al, Nucleic Acids Res. 24 (5), 843-849 (1996)
KIAA0346 / 41387— r_at / AB002344 / - / - / - interferon, alpha— inducible protein 27 / 425一 at / X67325 / MI_005532 / NP一 005523 I Rasmussen, U. B. et al, Cancer Res. 53 (17)， 4096-4101 (1993) bridging integrator 1， isoform 1 / 459— s一 at / AL713697 / 應一 139343 / NP _647593 I - bridging integrator 1, isoform 2 / 459— s— at / AF043901 / NM一 139344 / NP 一 647594 I - bridging integrator 1, isoform 3 / 459— s一 at / AF043899 / NM一 139345 / NP —647595 I - bridging integrator 1， isoform 4 / 459— s— at / AH006176 / NM— 139346 / NP .647596 I - bridging integrator 1， isoform 5 / 459— s一 at / AF043898 / NM— 139347 I NP 一 647597 I - bridging integrator 1， isoform 6 / 459— s一 at / AF001383 / NM— 139348 / NP —647598 I一 KIAA0346 / 41387— r_at / AB002344 /-/-/-interferon, alpha- inducible protein 27/425 at / X67325 / MI_005532 / NP 005523 I Rasmussen, UB et al, Cancer Res. 53 (17), 4096-4101 (1993) bridging integrator 1, isoform 1 / 459—s-at / AL713697 / Oichi139343 / NP_647593 I-bridging integrator 1, isoform 2 / 459—s—at / AF043901 / NM-139139344 / NP-647647 I- bridging integrator 1, isoform 3 / 459— s-at / AF043899 / NM-139345 / NP—647595 I-bridging integrator 1, isoform 4 / 459—s—at / AH006176 / NM—139346 / NP.647596 I-bridging integrator 1, isoform 5 / 459—s one at / AF043898 / NM—139347 I NP one 647597 I-bridging integrator 1, isoform 6 / 459—s one at / AF001383 / NM—139348 / NP—647598 I one
bridging integrator 1， isoform 7 / 459一 s一 at / AF043900 / NM— 139349 / NP —647599 / - bridging integrator 1, isoform 8 / 459一 s— at / U68485 / NM— 004305 / NP一 0 04296 I - bridging integrator 1, isoform 9 / 459一 s一 at / AF068914 / NM一 139350 I NP —647600 I一 bridging integrator 1, isoform 7 / 459-1 s-1 at / AF043900 / NM—139349 / NP—647599 /-bridging integrator 1, isoform 8 / 459-1 s—at / U68485 / NM—004305 / NP-1 0 04296 I-bridging integrator 1, isoform 9 / 459-1 s-1 at / AF068914 / NM-1 139350 I NP —647600 I-1
bridging integrator 1, isoform 10 / 459 s at / AF068915 / 丽— 139351 I N P— 647601 I - smooth muscle myosin heavy chain 11， isoform S 2 / 773_at / D10667 / NM —022844 I NP— 074035 /一 bridging integrator 1, isoform 10/459 s at / AF068915 / 丽 — 139351 IN P—647601 I-smooth muscle myosin heavy chain 11, isoform S 2 / 773_at / D10667 / NM —022844 I NP— 074035 / one
—データ 1 2 ： —Data 1 2:
(ァトピー性皮膚炎と乾癬患者の皮膚組織における遺伝子発現を健常者皮膚組 織と比較した結果、 乾癬患者の無疹部でのみ発現変動/低下が認められた遺伝 子）  (Comparing gene expression in skin tissues of patients with atopic dermatitis and psoriasis with healthy skin tissues, a gene whose expression was fluctuated / reduced only in the non-rash area of psoriatic patients)
H2B histone family, member G / 31522— f— at / Z80779 / NM— 003522 / NP— 003 513 I - cholinergic receptor, nicotinic, beta polypeptide 4 / 33568— at / U48861 I應 -000750 I NP— 000741 I一  H2B histone family, member G / 31522—f—at / Z80779 / NM—003522 / NP—003 513 I-cholinergic receptor, nicotinic, beta polypeptide 4 / 33568—at / U48861 Io-000750 I NP—000741 I
related to the N terminus of tre / 34594— at / D13644 / N一 014688 / NP一 0 55503 I Matoskova, B. et al, Oncogene 12 (12) , 2563-2571 (1996) related to the N terminus of tre / 34594— at / D13644 / N-014688 / NP 0 55503 I Matoskova, B. et al, Oncogene 12 (12), 2563-2571 (1996)
laminin, gamma 2 isoform b / 35281— at I U31201 / NM— 018891 / NP— 061486 I Kallunki, P. et al, J. Cell Biol. 119 (3)， 679-693 (1992) laminin, gamma 2 isoform b / 35281-at I U31201 / NM-018891 / NP-061486 I Kallunki, P. et al, J. Cell Biol. 119 (3), 679-693 (1992)
interleukin 8 / 35372— r— at / M17017 / NM— 000584 / NP— 000575 / Matsushim a, K. et al, J. Exp. Med. 167 (6)， 1883-1893 (1988) interleukin 8 / 35372—r—at / M17017 / NM—000584 / NP—000575 / Matsushima, K. et al, J. Exp. Med. 167 (6), 1883-1893 (1988)
Kruppel— like factor 4 (gut) / 36214— at / U70663 / NM— 004235 / NP— 004226 Kruppel—like factor 4 (gut) / 36214—at / U70663 / NM—004235 / NP—004226
I Yet SF et al, J. Biol. Chem. 273 (2) , 1026-1031 (1998) I Yet SF et al, J. Biol. Chem. 273 (2), 1026-1031 (1998)
Al strom syndrome 1 / 38343— at / AB002326 / NM— 015120 / NP— 055935 I - occludin / 38524— at / U49184 / NM— 002538 / NP— 002529 / Ando-Akatsuka, Y. et al, J. Cell Biol. 133 (1) , 43 - 47 (1996) Al strom syndrome 1 / 38343—at / AB002326 / NM—015120 / NP—055935 I-occcludin / 38524—at / U49184 / NM—002538 / NP—002529 / Ando-Akatsuka, Y. et al, J. Cell Biol. 133 (1), 43-47 (1996)
〔実施例 5〕 ヒトのアトピー性皮膚炎とマウス皮膚炎モデルの比較  [Example 5] Comparison of human atopic dermatitis and mouse dermatitis model
ヒトのァトピー性皮膚炎の皮膚検体を用いた遺伝子発現解析によって見出さ れた病態関連遺伝子の重要性を評価する目的で、 マウス皮膚炎モデルの遺伝子 発現解析を行い、 ヒトのアトピー性皮膚炎との比較を行った。
Figure imgf000295_0001
In order to evaluate the importance of pathologically relevant genes found by gene expression analysis using skin samples of human atopic dermatitis, we performed gene expression analysis of a mouse dermatitis model and A comparison was made.
Figure imgf000295_0001
DNFB反復塗布接触性皮膚炎モデルマウスは、 永井らの方法 （J Allergy Cl in Immunol 1997 Dec ; 100 (6 Pt 2) : S39 - 44) に従って作製した。  DNFB repeated application contact dermatitis model mice were prepared according to the method of Nagai et al. (J Allergy Cl in Immunol 1997 Dec; 100 (6 Pt 2): S39-44).
BALB/cマウス （c 1 . 7〜10週齢） の耳介部に週 1回の割合で合計 5回、 vehicl e (アセトンとォリーブオイルを 3 ： 1の割合で混合した溶媒） に溶解した 0. 1 5%の Dinitrofluorobenzene (DNFB)溶液 25 μ 1を塗布した。 BALB / c mice (. C 1 7 to 10 weeks old) Total 5 times auricles at a rate of once a week, vehicl e: was dissolved in (acetone and Oribuoiru 3 1 solvent mixture in a ratio of) 0 25 μl of 15% dinitrofluorobenzene (DNFB) solution was applied.
2回目の DNFB塗布 2 時間後から耳介の浮腫が観察され、 3、 4、 5回と塗布回 数を重ねるに従って塗布 24時間後の浮腫率も増加した。 一方、 vehicle塗布群 では耳浮腫は観察されなかった。 また、 血中の特異的 IgEおよび total IgE濃 度は、 DNFB塗布群で 5回目の DNFB塗布 時間後の測定で DNFB塗布前 （試験開 始時） に比べて著しい上昇が認められたのに対し、 vehicle塗布群では上昇が認 められなかった。 更に、 病理組織学的解析の結果、 5回目の DNFB塗布 24時間後 の耳介皮膚組織には炎症性細胞浸潤 （好中球、 好酸球など）、 表皮の肥厚が認め られ、 皮膚炎病態の形成が観察できた。  Ear edema was observed 2 hours after application of the second DNFB, and the edema rate increased 24 hours after application as the number of application times increased to 3, 4, and 5 times. On the other hand, no ear edema was observed in the vehicle application group. In addition, the level of specific IgE and total IgE in the blood was markedly higher in the DNFB-coated group compared to before DNFB-application (at the start of the test) when measured after the fifth DNFB-application time. However, no increase was observed in the vehicle application group. Furthermore, as a result of histopathological analysis, inflammatory cell infiltration (neutrophils, eosinophils, etc.) and epidermal hyperplasia were observed in the auricular skin tissue 24 hours after the fifth application of DNFB, and the dermatitis pathology was observed. Was observed.
DNFB塗布、 Vehicle塗布群からそれぞれ 2匹の個体を選択し、 1、 3、 5回目の 塗布前と塗布 4時間後の耳介皮膚を採取した。 マウス皮膚からのジーンチップ 解析用の RNA調製、 ジーンチップ用の cDNA合成、 DNAチップ解析は実施例 2に 従って行った。  Two individuals were selected from each of the DNFB-applied and Vehicle-applied groups, and the auricle skin was collected before the first, third, and fifth application and 4 hours after application. RNA preparation for gene chip analysis from mouse skin, cDNA synthesis for gene chip, and DNA chip analysis were performed according to Example 2.
DNFB反復塗布耳介皮膚 （接触性皮膚炎病変部） で発現変動する遺伝子とヒトァ トピー性皮膚炎皮膚組織で発現変動する遺伝子の比較  Comparison of genes whose expression is fluctuated in ear skin (contact dermatitis lesions) and those whose expression is fluctuated in human atopic dermatitis skin tissue
DNFB塗布耳介皮膚における遺伝子発現と Vehicle塗布耳介皮膚における遺伝 子発現を Comparison analysisによって比較解析し、 DNFB塗布 1、 3、 5回目の それぞれで塗布前と塗布 4時間後の比較で 2倍以上発現が増加している遺伝子 および 1/2 以下に発現が減少している遺伝子を急性病変部で変動する遺伝子と して選択した。 また、 3回目おょぴ 5回目の DNFB塗布前と 1回目の塗布前の比 較で 2倍以上発現が増加している遺伝子および 1/2以下に発現が減少している 遺伝子を慢性病変部で変動する遺伝子として選択した。 これら遺伝子群とヒトのアトピー性皮膚炎の無疹部と急性病変部間で発現変 動した遺伝子群を比較した結果を表 7 6〜表 8 2に示した。 共通変動を示した 遺伝子については、 このマウス皮膚炎モデルにおいてノックァゥトマウスある いはトランスジエニックマウスを作製することにより、 皮膚炎病態における重 要性を評価することができる。 また、 液性因子や膜蛋白質については皮膚炎モ デルマウスに中和抗体を投与、 あるいは液性因子そのものや可溶性膜蛋白質を 投与することにより、 その遺伝子の重要性を評価できる。 Comparative analysis of gene expression in DNFB-applied auricle skin and gene expression in Vehicle-applied auricle skin was performed by Comparison analysis, and the DNFB was more than doubled before, after and 4 hours after the first, third, and fifth application, respectively. Genes with increased expression and genes with less than 1/2 decrease in expression were selected as fluctuating genes in acute lesions. In addition, the genes whose expression is more than doubled and the gene whose expression is reduced by less than 1/2 compared with the 5th application of DNFB and before the 1st application of chronic lesions Was selected as a variable gene. Tables 76 to 82 show the results of comparison between these gene groups and the gene groups whose expression was fluctuated between the eruption-free area and the acute lesion of human atopic dermatitis. For genes showing common variation, the importance of dermatitis pathological conditions can be evaluated by producing knockout mice or transgenic mice in this mouse dermatitis model. For humoral factors and membrane proteins, the importance of the genes can be evaluated by administering neutralizing antibodies to dermatitis model mice or by administering humoral factors themselves or soluble membrane proteins.
表 7 6  Table 7 6
ヒトのアトピー性皮膚炎 （急性病変部と無疹部） と DNFB反復塗布マウス接触 性皮膚炎モデル （DNFB塗布耳介皮膚とコントロール Vehicle塗布耳介皮膚） 間 で共通変動 （増加） した遺伝子を示した。 表中に記載されている、 ΐ † ΐ ΐは 変動が 50倍以上、 卞は10〜50倍、 卞は3〜10倍、 †は 2〜3倍、 —は変 動なしであることを示す。 Genes that showed a common variation (increase) between human atopic dermatitis (acute lesions and no eruptions) and DNFB-repeated mouse contact dermatitis model (DNFB-coated auricle skin and control vehicle-coated auricle skin) Was. In the table, ΐ † ΐ ΐ indicates that the fluctuation is 50 times or more, Bya indicates 10 to 50 times, Byon indicates 3 to 10 times, † indicates 2-3 times, and — indicates no fluctuation .
TTTT J- Ί· Ί-♦ 1/50倍以下 TTTT J- Ί
ΤΤί ill 1/50〜1/10倍  ΤΤί ill 1 / 50-1 / 10
U 1/10〜1/3倍 1/3〜1/2倍  U 1 / 10-1 / 3 times 1 / 3-1 / 2 times
32 5変 1 32 5 odd 1
動倍？"  Moving? "
き¾な倍以  More than double
咅し上  On top
Figure imgf000297_0001
Figure imgf000297_0001
S100 family proteins ( small(10-14kDa) calcium jinding protein ) S100 family proteins (small (10-14kDa) calcium jinding protein)
41096一 at ίί ίίΐ ίίί ί r ίί Τίί ίί ίίί it T† ίί ίΤ Μ83218 ΑΙ126134  41096 ichi at ίί ίίΐ ίίί ί r ίί Τίί ίί ίίί it T † ίί ίΤ Μ83218 ΑΙ126134
41471 at m ίίί Τίίί ίΐί ί ίί it ίίίί Τίί T††t Τΐί ί m Μ83219 W72424 41471 at m ίίί Τίίί ίΐί ί ίί it ίίίί Τίί T †† t Τΐί ί m Μ83219 W72424
CD antigen, Immunoglobulin— ike receptor CD antigen, Immunoglobulin— ike receptor
31438 s at ί † † ί ίί ίί ΑΙ450439 Ζ22971 31438 s at ί † † † ίί ίί ίί 450439 Ζ22971
38378一 at ίΤ τ ί t ΐίί ί ίίί t ί TT Χ97227 Μ3703338378 i at τ τ ί t ΐίί ί ίίί t ί TT Χ97227 Μ37033
Kinase and Phosphatase ο Kinase and Phosphatase ο
1402— at - ί † I ίί ί † I - I †† I - I ίί I ί ί Μ57696 Μ16038 1402— at--† I ίί ί † I-I †† I-I ίί I ί ί 9657696 Μ16038
Enzyme ( without protease, kinase, natase ) Enzyme (without protease, kinase, natase)
32363 at T† Τΐ n ί ττ ίΐ ΐί Τΐ ττ AF059213 AF059214 32363 at T † Τΐ n ί ττ ίΐ ΐί τ ττ AF059213 AF059214
32775 r at † τί ί ΐ ίί ί ττ D78354 ΑΒ00674632775 r at ί τί ΐ ΐ ίί ττ D78354 ΑΒ006746
34666 at ίί ίί ίί ίί it t ίίί ίίί ίί L35528 Χ0783434666 at ίί ίί ίί ίί it t ίίί ίίί ίί L35528 Χ07834
Cytoskeletal structural protein, cytoskeleton associated protein Cytoskeletal structural protein, cytoskeleton associated protein
39015 f at ίΐ ίί ΐΐ ττ ίί ίΐ ττ ίί τ K02108 L426 1 39015 f at ίΐ ίί ΐΐ ττ ίί τ ττ τ τ K02108 L426 1
37473 at †t ίί m ίί ίί ίί ίίί †t rt ίί ίί ηί AF053235 AF06181237473 at † t ίί m ίί ίί ίί ίίί t rt ίί ί ηί AF053235 AF061812
37160 at ίΐ T† ττ τ † τ Τί ί ίί rr 言 ΐ ††† Τί Χ91825 1988837160 at ίΐ T † ττ τ † τ Τί ί rr rr Word ΐ ††† Τί Χ91825 19888
Interferon-inducible protein Interferon-inducible protein
1 107_s_at - - ίί - I ί I - I ίί I †t Π I m ί - - 1 TT 1 - - AV152244 Μ13755 1 107_s_at--ίί-I ί I-I ίί I † t Π I m ί--1 TT 1--AV152244 Μ13755
G— protein and related molecule G— protein and related molecule
33371 s at - T Τ τ - τ - TT - Τΐ τ - - I Τί - - AV245978 U59877  33371 s at-T τ τ-τ-TT-Τΐ τ--I Τί--AV245978 U59877
Others Others
32598 at ί τ ίί ίί † t 言言 ίΐ ίί ί U59230 D83018 32598 at τ τ ίί ίί † t Language ίΐ ίί ί U59230 D83018
37759 at ίΐ ί t ί ΐΐ † ίί ί ί ίί AV330551 U5124037759 at ίΐ ί t ί ΐΐ † ίί ί ί ίί AV330551 U51240
38489 at ίί ΐ ί ίί ΐί †† U it AF065441 Μ6004738489 at ίί ΐ ί ίί ίί ΐί it U it AF065441 Μ60047
39591 s at †i † ί η † ίί † Ml 6238 Ζ36531 39591 s at † i † ί η † ίί l Ml 6238 Ζ36531
77. L 77. L
表 7 8  Table 7 8
ヒトのアトピー性皮膚炎 （急性病変部と無疹部） と DNFB反復塗布マウス接触 性皮膚炎モデル (DNFB塗布耳介皮膚とコントロール Vehicle塗布耳介皮膚） 間 で共通変動 （増加） した遺伝子 （表 7 6〜表 7 7 ) の説明を示した。 Genes (Tables) that were commonly altered (increased) between human atopic dermatitis (acute lesions and eruptions) and DNFB-repeated mouse contact dermatitis models (DNFB-coated auricle skin and control vehicle-coated auricle skin) The explanations from 76 to Table 77) are given.
表し一 1(D): ヒ卜のアトピー性皮膚炎（急性病変部と無疹部）と DNFB反復塗布 BALB/cマウス接触性皮膚炎モデル Representation 1 (D): Atopic dermatitis in humans (acute lesions and no eruptions) and repeated application of DNFB BALB / c mouse contact dermatitis model
(DNFB塗布耳介皮膚とコントロール耳介皮膚)間で共通変動した遺伝子  Genes commonly fluctuated between (DNFB-coated auricle skin and control auricle skin)
Increase  Increase
Human Mouse Human  Human Mouse Human
Probe ID accession accession Descripticms  Probe ID accession accession Descripticms
Protease and associated molecule  Protease and associated molecule
1482一 g— at M82831 L23808 metalloproteinase (HME)  1482 one g—at M82831 L23808 metalloproteinase (HME)
32514 s at AJ242663 AF032906 cathepsin Z precursor (CTSZ)  32514 s at AJ242663 AF032906 cathepsin Z precursor (CTSZ)
37137 at M 12302 17016 serine protease-like protein  37137 at M 12302 17016 serine protease-like protein
37554 at Y18723 U62801 protease M  37554 at Y18723 U62801 protease M
32821 at X81627 AI762213 neutrophil gelatinase associated lipocalin  32821 at X81627 AI762213 neutrophil gelatinase associated lipocalin
Protease inhibitor  Protease inhibitor
1693 s at V00755 D1 1139 tissue inhibitor of metalloproteinases  1693 s at V00755 D1 1139 tissue inhibitor of metalloproteinases
CD  CD
Cytokine, Cytokine Receptor (Growth factorも含む) CD Cytokine, Cytokine Receptor (including Growth factor) CD
404一 at M27960 X52425 interleukin 4 receptor 404 one at M27960 X52425 interleukin 4 receptor
33849 at AI852144 U02020 pre - B cell enhancing factor (PBEF)  33849 at AI852144 U02020 pre-B cell enhancing factor (PBEF)
38037 at AV217847 M60278 heparin— binding EGFHike growth factor  38037 at AV217847 M60278 heparin—binding EGFHike growth factor
37493 at M34397 H04668 GM-CSFR beta  37493 at M34397 H04668 GM-CSFR beta
Chemokine, Chemokine receptor  Chemokine, Chemokine receptor
32128 at J04491 Y13710 alternative activated macrophage specific CC chemokine 1  32128 at J04491 Y13710 alternative activated macrophage specific CC chemokine 1
875_g_at M19681 M26683 MCP-1  875_g_at M19681 M26683 MCP-1
37187 at X53798 M36820 GRO - beta  37187 at X53798 M36820 GRO-beta
39994 at U29678 D 10925 CCR1  39994 at U29678 D 10925 CCR1
408 at AA174767 X54489 melanoma growth stimulatory activity (MGSA) / Gro 0£  408 at AA174767 X54489 melanoma growth stimulatory activity (MGSA) / Gro 0 £
S100 family proteins ( smalldO- 14 <Da) calcium binding protein )  S100 family proteins (smalldO- 14 <Da) calcium binding protein)
41096 at M83218 AI126134 MRP- 8 (S100A8)  41096 at M83218 AI126134 MRP-8 (S100A8)
41471 at M83219 W72424 MRP-14CS100A9)  41471 at M83219 W72424 MRP-14CS100A9)
CD antigen, Immunoglobulin— like receptor  CD antigen, Immunoglobulin-- like receptor
31438 s at AI450439 Z22971 M130 antigen extracellular variant / CD163 31438 s at AI450439 Z22971 M130 antigen extracellular variant / CD163
38378 at X97227 37033 CDo3 glycoprotein 38378 at X97227 37033 CDo3 glycoprotein
Kinase and Phosphatase Kinase and Phosphatase
1402 at 57696 Ml 6038 lyn  1402 at 57696 Ml 6038 lyn
Enzyme ( without protease, kinase , phosphatase )  Enzyme (without protease, kinase, phosphatase)
32363 at AF059213 AF059214 cholesterol 25-hydroxylase  32363 at AF059213 AF059214 cholesterol 25-hydroxylase
32775 r at D78354 AB006746 Phospholipid scramblase 1  32775 r at D78354 AB006746 Phospholipid scramblase 1
34666 at L35528 X07834 manganese superoxide dismutase (EC 1.15.1.1)  34666 at L35528 X07834 manganese superoxide dismutase (EC 1.15.1.1)
Cytoskelel al structural protein, cytoskeleton associated protein Cytoskelel al structural protein, cytoskeleton associated protein
39015 f at K02108 L42611 keratin 6A O 39015 f at K02108 L42611 keratin 6A O
37473 at AF053235 AF061812 keratin 16 o o37473 at AF053235 AF061812 keratin 16 o o
37160 at X91825 M19888 small proline-rich protein 1B (cornifin) 37160 at X91825 M19888 small proline-rich protein 1B (cornifin)
Interferon-inducible protein Interferon-inducible protein
1 107 s at AVI 52244 M13755 interferon-induced 17~kDa/15-kDa protein  1 107 s at AVI 52244 M13755 interferon-induced 17 ~ kDa / 15-kDa protein
G - protein and related molecule G-protein and related molecule
33371_s_at AV245978 U59877 RAB31  33371_s_at AV245978 U59877 RAB31
Others Others
32598 at U59230 D83018 nel-related protein 2  32598 at U59230 D83018 nel-related protein 2
37759— at AV330551 U51240 lysosomaト associated multitransmembrane protein (LAPTm5)  37759—at AV330551 U51240 lysosoma to associated multitransmembrane protein (LAPTm5)
38489 at AF065441 M60047 heparin binding protein (HBp17) 1 FGF-BP1  38489 at AF065441 M60047 heparin binding protein (HBp17) 1 FGF-BP1
39591_s_at M16238 Z36531 fibrinogen - like 2  39591_s_at M16238 Z36531 fibrinogen-like 2
9 表 8 0 9 Table 80
ヒトのアトピー性皮膚炎 （急性病変部と無疹部） と DNFB反復塗布マウス接触 性皮膚炎モデル (DNFB塗布耳介皮膚とコントロール Vehicle塗布耳介皮膚） 間 で共通変動 （減少） した遺伝子を示した。 表中に記載されている、 丄 丄 丄 丄は 1 /50倍以下、 丄 丄 丄は 1/50〜1/10倍、 1 1は 1/10〜1ノ 3倍、 丄は 1/3〜1/2倍、 -は変動なしであることを示す。 Genes that showed a common variation (decrease) between human atopic dermatitis (acute lesions and no eruptions) and DNFB-repeated mouse contact dermatitis model (DNFB-coated auricle skin and control vehicle-coated auricle skin) Was. In the table, 丄 丄 1 丄 is 1/50 or less, 丄 丄 1 is 1/50 to 1/10, 1 1 is 1/10 to 1 × 3, 丄 is 1/3 to 1/2 times,-indicates no change.
TTTT 50倍以上 UU 1/50倍以下 TTTT 50 times or more UU 1/50 times or less
ίΤΤ 10- 50倍 * J* 1/50〜1/10倍  ίΤΤ 10-50 times * J * 1 / 50-1 / 10 times
ίί 3-10倍 U 1 Ί0〜1/3倍  ίί 3-10 times U 1 Ί0〜1 / 3 times
τ 2-3倍 1 1/3~1/2倍  τ 2-3 times 1 1/3 ~ 1/2 times
変動なし  No change
表し -2 : ヒトのアトピー性皮膚炎 (急性病変部と無疹部）と DNFB反復塗布 BALB/cマウス接触性皮膚炎モデル (DNFB塗布耳介皮膚と Representation -2: Human atopic dermatitis (acute lesions and eruptions) and DNFB repeated application BALB / c mouse contact dermatitis model (DNFB applied auricular skin
コントロール耳介皮膚〉間で共通変動した遺伝子（無疹部に比べて皮疹部で発現が低下していた遺伝子）  Genes that fluctuated in common between control auricle skin (genes whose expression was lower in the rash than in the rash)
Decrease (無疹部 >皮疹部） Decrease (no rash> rash)
Human Human ouse Human  Human Human ouse Human
case Acute Chronic  case Acute Chronic
Probe ID 2 3 I 4 6 . 9 10 12 13 15 16 17 1W 3W I 5W 3W I 5W accession accession Probe ID 2 3 I 46 .9 10 12 13 15 16 17 1W 3W I 5W 3W I 5W accession accession
Cytoskeletal structural protein, cytoskeleton associated protein Cytoskeletal structural protein, cytoskeleton associated protein
37582 at 1 in i I a u u i AV171812 X07696 37582 at 1 in i I a u u i AV171812 X07696
35105— at 1 ii ii i i u u 1 u i AA727482 AF045941 ω o35105—at 1 ii ii i i u u 1 u i AA727482 AF045941 ω o
Kinase and Phosphatase Kinase and Phosphatase
40524 at i u 1 u i ii i D37801 X79510 40524 at i u 1 u i ii i D37801 X79510
33787 at 1 u 1 i u ii i AW494241 AB01 1 10933787 at 1 u 1 i u ii i AW494241 AB01 1 109
Apolipoprotein Apolipoprotein
36681 at 一 一 i 一 i i — Ui 丄 u - - - - - i X82648 J02611 36681 at one one i one i i — Ui 丄 u-----i X82648 J02611
Transcription factor and related mo ecule (1 ranscriptional re gulator protein ) Transcription factor and related mo ecule (1 ranscriptional regulator protein)
40511 at u i i ii u i ii i i X55123 X58072 40511 at u i i ii u i ii i i X55123 X58072
41536 at ΪΪ u ii ii i ii ii i AJ001972 AL02272641536 at ΪΪ u ii ii i ii ii i AJ001972 AL022726
Others Others
Membrane protein  Membrane protein
38821 at ii 1 i i i ii I AI607332 AJ002030 38821 at ii 1 i i i ii I AI607332 AJ002030
34412 s at i u u u i i AF033350 U5963234412 s at i u u u i i AF033350 U59632
Secreted protein Secreted protein
40658— at — — U ill U U U 一 U iii - - I - - - U49915 D45371 40658—at — — U ill U U U ichi U iii--I---U49915 D45371
Others Others
CO
Figure imgf000304_0001
CO
Figure imgf000304_0001
W 200 W 200
304| ί 304 | ί
表 82  Table 82
ヒトのアトピー性皮膚炎 （急性病変部と無疹部） と DNFB反復塗布マウス接触 性皮膚炎モデル （DNFB塗布耳介皮膚とコントロール Vehicle塗布耳介皮膚） 間 で共通変動 （減少） した遺伝子 （表 80〜表 81) の説明を示した。 Genes (Tables) that showed a common variation (decrease) between human atopic dermatitis (acute lesions and no eruptions) and DNFB-repeated mouse contact dermatitis model (DNFB-coated auricle skin and control vehicle-coated auricle skin) 80 to Table 81).
表 L- 2(D) : ヒ卜のアトピー性皮膚炎 (急性病変部と無疹部)と DNFB反復塗布 BALB/cマウス接触性皮膚炎モデル Table L-2 (D): Atopic dermatitis in humans (acute lesions and no eruptions) and DNLB repeated application BALB / c mouse contact dermatitis model
(DNFB塗布耳介皮膚とコントロール耳介皮膚)間で共通変動した遺伝子  Genes commonly fluctuated between (DNFB-coated auricle skin and control auricle skin)
Decrease  Decrease
Human Mouse Human  Human Mouse Human
Probe ID accession accession Descriptions  Probe ID accession accession Descriptions
Cytoskeletal structure protein, cy toskeleton associated protein  Cytoskeletal structure protein, cy toskeleton associated protein
37582 at AV171812 X07696 cytokeratin 15  37582 at AV171812 X07696 cytokeratin 15
35105一 at AA727482 AF045941 sciellin (SCEL)  35105 ichi at AA727482 AF045941 sciellin (SCEL)
Kinase and Phosphatase Kinase and Phosphatase
40524 at D37801 X79510 'protein - tyrosine - phosphatase D1  40524 at D37801 X79510 'protein-tyrosine-phosphatase D1
33787 at AW494241 AB01 1 109 KIAA0537  33787 at AW494241 AB01 1 109 KIAA0537
CO  CO
Apolipoprotein 〇  Apolipoprotein 〇
CJl CJl
36681 at X82648 J0261 1 apolipoprotein D 36681 at X82648 J0261 1 apolipoprotein D
1 ranscription factor and related molecule (Transcriptional regulator protein ) 1 ranscription factor and related molecule (Transcriptional regulator protein)
4051 1 at X55123 X58072 GATA3  4051 1 at X55123 X58072 GATA3
41536 at AJ001972 AL022726 Inhibitor of DNA binding 4 ( ID4 )  41536 at AJ001972 AL022726 Inhibitor of DNA binding 4 (ID4)
Others Others
Membrane protein  Membrane protein
38821 at AI607332 AJ002030 progesterone receptor membrane component 2  38821 at AI607332 AJ002030 progesterone receptor membrane component 2
34412 s at AF033350 U59632 peanut-like 1 (Drosophila)  34412 s at AF033350 U59632 peanut-like 1 (Drosophila)
Secreted protein  Secreted protein
40658 r at U49915 D45371 ap 1( adipose most abundant gene transcript 1 )  40658 r at U49915 D45371 ap 1 (adipose most abundant gene transcript 1)
Others  Others
38851 at U09189 M63394 loricrin  38851 at U09189 M63394 loricrin
34445一 at AA163268 AB007940 KIAA0471 34445 one at AA163268 AB007940 KIAA0471
また以上の解析の結果に基づいて、 皮膚炎に関連するマウス由来の遺伝子と して次に示す遺伝子を同定した。 これらの遺伝子は、 いずれも本発明における 指標遺伝子として用いることができる。 以下に示す各遺伝子のデータは、 いず れも、 左から順に次の情報を記載している。 各情報はスラッシュ （/) で区切つ て示している。 各遺伝子の機能は、 対応するヒト遺伝子の記载に基づいて明ら かにすることができる。 Further, based on the results of the above analysis, the following genes were identified as genes derived from mice related to dermatitis. Any of these genes can be used as an indicator gene in the present invention. In the data of each gene shown below, the following information is described in order from the left. Each piece of information is separated by a slash (/). The function of each gene can be determined based on the description of the corresponding human gene.
「マゥス遺伝子名およぴシンボル」  "Mass gene name and symbol"
「プローブ」 （GeneChipにおけるプロ一プ ID)  "Probe" (Prop ID in GeneChip)
「プローブの塩基配列のデザインのために用いられた塩基配列のデータベース (GenBank)ァクセッションナンパー」  "Database of base sequence used for probe base sequence design (GenBank) accession number"
「各指標遺伝子の塩基配列のデータベース (GenBank)ァクセッションナンパ一」 「当該遺伝子の塩基配列を示す配列番号」  "Base sequence database of each index gene (GenBank) accession number" "SEQ ID NO: indicating the base sequence of the gene"
「各指標遺伝子によってコードされるァミノ酸配列のデータベース（GenBank)ァ クセッションナンバ一」  "Database of amino acid sequences encoded by each indicator gene (GenBank) accession number"
「当該遺伝子によつてコードされるァミノ酸配列を示す配列番号」  "SEQ ID NO: indicating the amino acid sequence encoded by the gene"
「ReferenCe」 （当該遺伝子を報告した論文） "Refer e n Ce" (paper that reported the gene)
「対応するヒト遺伝子のデータベース（GenBank)ァクセッションナンパ一」 「対応するヒト遺伝子の遺伝子名」  "Corresponding human gene database (GenBank) accession number" "Corresponding human gene name"
一データ 1 3 ： One data 1 3:
(ヒトのアトピー性皮膚炎 （急性病変部と無疹部比較） と BALB/Cマウス接触 '[4 膚炎モデル （ダニ感作耳介皮膚と非感作耳介皮膚比較） 間で共通変動 Z上昇し た遺伝子群のマウス遺伝子）  (Common variation between human atopic dermatitis (comparison of acute lesions and eruptions) and BALB / C mouse contact [4 Dermatitis model (comparison of tick-sensitized and non-sensitized auricle skin) Z] Mouse genes of the elevated gene group)
matrix metalloproteinase 12 / 95339— r一 at / M82831 / NM—008605 / 01. nuc / NP_032631 / 01. AA / Shapiro, S. D. et al, J. Biol. Chem. 267 (7) , 4664 - 4671 (1992) I L23808 / metalloproteinase (HME) matrix metalloproteinase 12 / 95339-r-at / M82831 / NM-008605 / 01.nuc / NP_032631 / 01.AA / Shapiro, SD et al, J. Biol. Chem. 267 (7), 4664-4671 (1992) I L23808 / metalloproteinase (HME)
cathepsin Z / 92633— at I AJ242663 /画一 022325 / 02. nuc / NP_071720 I 02. AA I Deussing J. et al, Biochim. Biophys. Acta 1491 (1-3) , 93 - 106 (200 0) / AF032906 / cathepsin Z precursor (CTSZ) cathepsin Z / 92633—at I AJ242663 / Ichi 022325 / 02.nuc / NP_071720 I 02. AA I Deussing J. et al, Biochim. Biophys. Acta 1491 (1-3), 93-106 (200 0) / AF032906 / cathepsin Z precursor (CTSZ)
Granzyme B / 102877— at I M12302 / NM一 013542 / 03. nuc / NP— 038570 / 03. A A I Lobe, CG, et al, Science 232, 858—861 (1986) / M17016 / serine prot ease-like protein (granzyme B)  Granzyme B / 102877—at I M12302 / NM 013542 / 03.nuc / NP — 038570 / 03.AAI Lobe, CG, et al, Science 232, 858—861 (1986) / M17016 / serine prot ease-like protein ( granzyme B)
protease, serine, 18 / 92353一 at / Y18723 /應— 011177 / 04. nuc / NP— 0353 07 I 04. AA / Meier, N. et al, Biochera. Biophys. Res. Commun. 258 (2) , 37 4-378 (1999) / U62801 / protease M Protease, serine, 18 / 92353-at / Y18723 / O—0111177 / 04.nuc / NP—0353 07 I 04.AA / Meier, N. et al, Biochera. Biophys. Res.Commun. 258 (2), 37 4-378 (1999) / U62801 / protease M
lipocalin 2 I 160564— at / X81627 /— / 05. nuc / CAA57283 / 05. AA / Gara y-Ro jas, E. et al, Gene 170 (2)， 173-180 (1996) / AI762213 / neutrophil gelatinase associated lipocalin (NGAL) lipocalin 2 I 160564—at / X81627 / — / 05.nuc / CAA57283 / 05.AA / Gara y-Ro jas, E. et al, Gene 170 (2), 173-180 (1996) / AI762213 / neutrophil gelatinase associated lipocalin (NGAL)
tissue inhibitor of metalloproteinase 1 / 101464— at / V00755 / M—01159 3 I 06. nuc I NP一 035723 / 06. AA / Edwards, D. R. et al, Nucleic Acids Res.tissue inhibitor of metalloproteinase 1 / 101464— at / V00755 / M-01159 3 I 06. nuc I NP 035723 / 06. AA / Edwards, D.R. et al, Nucleic Acids Res.
14 (22) , 8863-8878 (1986) / D11139 / tissue inhibitor of metalloprotei nases 14 (22), 8863-8878 (1986) / D11139 / tissue inhibitor of metalloprotei nases
interleukin 4 receptor, alpha / 102021一 at / 27960 / NM— 010557 / 07. nuc I NP一 034687 / 07. AA / Mosley, B. et al, Cell 59， 335-348 (1989) / X524 25 I IL-4R interleukin 4 receptor, alpha / 102021 at / 27960 / NM— 010557 / 07.nuc I NP 034687 / 07.AA / Mosley, B. et al, Cell 59, 335-348 (1989) / X524 25 I IL- 4R
pre- B - cell colony-enhancing factor I 94461— at / AI852144 / NM— 021524 / 08. nuc I NP— 067499 / 08. AA / - / U02020 I pre- B cell enhancing factor (PBEF) pre- B-cell colony-enhancing factor I 94461— at / AI852144 / NM— 021524 / 08.nuc I NP— 067499 / 08. AA /-/ U02020 I pre-B cell enhancing factor (PBEF)
heparin binding epidermal growth factor-like growth factor / 168365一 at I AV217847 / 丽— 010415 I 09. nuc / NP— 034545 / 09. M / Abraham, J. A. et a 1, Biochem. Biophys. Res. Commun. 190 (1) , 125 - 133 (1993) I M60278 / he par in-binding EGF - like growth factor heparin binding epidermal growth factor-like growth factor / 168365-I at I AV217847 / 丽-010415 I 09. nuc / NP- 034545 / 09. M / Abraham, JA et a 1, Biochem. Biophys. Res. Commun. 190 (1 ), 125-133 (1993) I M60278 / he par in-binding EGF-like growth factor
colony stimulating factor 2 receptor, beta 1, low-affinity (granulocyte- macrophage) / 113724_at / M34397 / 丽— 007780 / 10. nuc / NP— 031806 / 10. AA I Gorman, DM, et al, Proc. Natl. Acad. Sci. U. S. A. 87， 5459-5463 (19 90) I 腿 668 I GM-CSFR beta colony stimulating factor 2 receptor, beta 1, low-affinity (granulocyte- macrophage) / 113724_at / M34397 / 丽 —007780 / 10.nuc / NP—031806 / 10.AA A Gorman, DM, et al, Proc. Natl. Acad. Sci. USA 87, 5459-5463 (1990) I thigh 668 I GM-CSFR beta
chemokine (C-C motif) ligand 3 / 102424— at I J04491 / NM一 011337 / 11. nu c I NP一 035467 / 11. AA / Davatelis, G. et al, J. Exp. Med. 167 (6)， 1939 - 1944 (1988) / Y13710 / alternative activated macrophage specific CC che mokine 1 chemokine (CC motif) ligand 3 / 102424—at I J04491 / NM-1 011337 / 11.nucl I NP035467 / 11. AA / Davatelis, G. et al, J. Exp. Med. 167 (6), 1939 -1944 (1988) / Y13710 / alternative activated macrophage specific CC che mokine 1
MCP-1 / 102736— at / M19681 I NM一 011333 / 12. nuc / NP— 035463 / 12. AA / K awahara, RS. and Deuel, TF. J. Biol. Chem. 264， 679—682 (1989) / M26683 / MCP-1  MCP-1 / 102736—at / M19681 I NM-1 011333 / 12.nuc / NP—035463 / 12.AA / Kawahara, RS. And Deuel, TF. J. Biol. Chem. 264, 679—682 (1989) / M26683 / MCP-1
Macrophage inflammatory protein 2 / 101160一 atノ X53798 / NM— 009140 I 13. nuc / NP一 033166 / 13. AA / Tekamp-Olson, P. et al, J. Exp. Med. 172, 911一 919 (1990) I M36820 / GRO-beta  Macrophage inflammatory protein 2/101160-at no X53798 / NM-009140 I 13.nuc / NP-033166 / 13.AA / Tekamp-Olson, P. et al, J. Exp. Med. 172, 911-919 (1990) I M36820 / GRO-beta
Chemokine (C-C) receptor 1 I 99413— at / U29678 / NM_009912 / 14. nuc / N P— 034042 I 14. AA / Gao, JL. and Murphy, PM. J. Biol. Chem. 270, 17494-17 501 (1995) / D10925 / CCRl  Chemokine (CC) receptor 1 I 99413—at / U29678 / NM_009912 / 14.nuc / NP—034042 I 14.AA / Gao, JL. And Murphy, PM.J.Biol.Chem. 270, 17494-17 501 (1995 ) / D10925 / CCRl
chemokine (C一 X— C motif) ligand 11 / 140659一 at / AA174767 / NM— 019494 I 15. nuc I NP— 062367 / 15. AA / Meyer, M. et al, Cytogenet. Cell Genet. 88 (3—4) , 278-282 (2000) / X54489 / melanoma growth stimulatory activity (MGSA) Gro alpha chemokine (C-X—C motif) ligand 11/140659 at / AA174767 / NM—019494 I 15.nuc I NP—0662367 / 15 AA / Meyer, M. et al, Cytogenet.Cell Genet. 88 (3— 4), 278-282 (2000) / X54489 / melanoma growth stimulatory activity (MGSA) Gro alpha
intracellular calcium-binding protein (MRP8) / 103448— at / M83218 / NM— 013650 I 16. nuc I NP— 038678 / 16. M / Lagasse, E. and Weissman, IL. Bloo d 79, 1907—1915 (1992) I AI126134 I MRP— 8 intracellular calcium-binding protein (MRP8) / 103448— at / M83218 / NM— 013650 I 16. nuc I NP— 038678 / 16. M / Lagasse, E. and Weissman, IL.Blood 79, 1907—1915 (1992) I AI126134 I MRP— 8
intracellular calcium-binding protein (MRP 14) / 103887一 at / M83219 / 雇 —009114 I 17. nuc I NP— 033140 I 17. AA / Lagasse, E. and ffeissraan, IL. Bio od 79， 1907-1915 (1992) / W72424 / MRP - 14 CD163 antigen / 115652— at / AI450439 / M_053094 / 18. nuc / NP— 444324 / 18. AA I Schaer, D. J. et al, Immunogenetics 53 (2) , 170-177 (2001) / Z22 971 I M130 antigen extracellular variant CD163 intracellular calcium-binding protein (MRP 14) / 103887 at / M83219 / hired — 009114 I 17. nuc I NP — 033140 I 17. AA / Lagasse, E. and ffeissraan, IL. Bio od 79, 1907-1915 (1992 ) / W72424 / MRP-14 CD163 antigen / 115652-- at / AI450439 / M_053094 / 18.nuc / NP-444324 / 18.AA I Schaer, DJ et al, Immunogenetics 53 (2), 170-177 (2001) / Z22 971 I M130 antigen extracellular variant CD163
CD53 / 94939一 at / X97227 / NM— 007651 / 19. nuc / NP一 031677 / 19. AA / Wri ght, MD. et al, Int. Immunol. 5, 209-216 (1993) / M37033 / CD53  CD53 / 94939-at / X97227 / NM—007651 / 19.nuc / NP-0131677 / 19.AA / Wri ght, MD.et al, Int. Immunol. 5, 209-216 (1993) / M37033 / CD53
Lyn I 103349一 at / M57696 /— / 20. nuc /— / 20. AA / Yi, T.し et al, Mol. Cell. Biol. 11 (5) , 2391 - 2398 (1991) / Ml 6038 / lyn Lyn I 103349 at / M57696 / — / 20.nuc / — / 20.AA / Yi, T.shi et al, Mol.Cell.Biol. 11 (5), 2391-2398 (1991) / Ml 6038 / lyn
cholesterol 25 - hydroxylase / 104509一 at / AF059213 / NM— 009890 / 21. nuc / NP一 034020 / 21. AA / Lund, E. G. et al, J. Biol. Chem. 273 (51) , 34316-3 4327 (1998) / AF059214 / cholesterol 25 - hydroxylase cholesterol 25-hydroxylase / 104509 at / AF059213 / NM— 009890 / 21.nuc / NP 034020 / 21. AA / Lund, EG et al, J. Biol. Chem. 273 (51), 34316-3 4327 (1998 ) / AF059214 / cholesterol 25-hydroxylase
phospholipid scramblase 1 / 102839一 at / D78354 / NM_011636 / 22. nuc / N P— 035766 / 22. AA / Wiedmer, T. et al, Biochim. Biophys. Acta 1467 (1) , 2 44-253 (2000) / AB006746 / Phospholipid scramblase 1 phospholipid scramblase 1/102839 at / D78354 / NM_011636 / 22.nuc / NP— 035766 / 22.AA / Wiedmer, T. et al, Biochim.Biophys. Acta 1467 (1), 244-253 (2000) / Phospholipid scramblase 1
superoxide dismutase 2， mitochondrial / 96042— at / L35528 / NM_013671 /superoxide dismutase 2, mitochondrial / 96042—at / L35528 / NM_013671 /
23. nuc I NP_038699 / 23. AA / Jones, P. L. et al, Gene 153 (2)， 155—161 (1 995) / X07834 / manganese superoxide dismutase (EC 1. 15. 1. 1) 23. nuc I NP_038699 / 23. AA / Jones, P.L. et al, Gene 153 (2), 155-161 (1 995) / X07834 / manganese superoxide dismutase (EC 1.15.1.1)
keratin complex 2, basic, gene 6a I 104370— s— at / K02108 / NM— 008476 / 24. nuc I NP_032502 / 24. AA / Steinert, P. M. et al, Proc. Natl. Acad. Sci.keratin complex 2, basic, gene 6a I 104370—s—at / K02108 / NM—008476 / 24.nuc I NP_032502 / 24.AA / Steinert, P.M. et al, Proc. Natl. Acad. Sci.
U. S. A. 81 (18) , 5709-5713 (1984) I L42611 / keratin 6A U.S.A. 81 (18), 5709-5713 (1984) I L42611 / keratin 6A
keratin 16 / 103589— at / AF053235 I NM— 008470 / 25. nuc / NP— 032496 I 25. AA I Porter, RM. et al, J. Biol. Chem. 273, 32265-32272 (1998) I AF0618 12 I keratin 16 (KRT16A) keratin 16 / 103589—at / AF053235 I NM—008470 / 25.nuc / NP—032496 I 25.AA I Porter, RM. et al, J. Biol. Chem. 273, 32265-32272 (1998) I AF0618 12 I keratin 16 (KRT16A)
small proline— rich protein IB / 100445— f— at / X91825 / NM— 009265 I 26. n uc I NP— 033291 / 26. AA / Kartasova, T. et al, J. Invest. Dermatol. 106, 294-304 (1996) / M19888 / small proline— rich protein IB (cornifin) Interferon— stimulated protein 15 / 161511— f— at / AVI 52244 / - / 27. nuc
Figure imgf000311_0001
small proline—rich protein IB / 100445—f—at / X91825 / NM—009265 I 26.nuc I NP—033291 / 26.AA / Kartasova, T. et al, J. Invest. Dermatol. 106, 294-304 (1996) / M19888 / small proline— rich protein IB (cornifin) Interferon— stimulated protein 15/161511 — f— at / AVI 52244 /-/ 27. nuc
Figure imgf000311_0001
/ - / 27. M / - / M13755 I interferon - induced 17-kDa 15-kDa protein RIKEN cDNA 1700093E07 gene I 161380— f一 at / AV245978 / NM_133685 / 28. nu c I NP— 598446 / 28. AA / Shibata, K. et al, Genome Res. 10 (11) , 1757 - 177 1 (2000) I U59877 / RAB31  /-/ 27. M /-/ M13755 I interferon-induced 17-kDa 15-kDa protein RIKEN cDNA 1700093E07 gene I 161380— f at at / AV245978 / NM_133685 / 28.nucl I NP— 598446/28. , K. et al, Genome Res. 10 (11), 1757-177 1 (2000) I U59877 / RAB31
nel - like 2 homolog (chicken) I 92358— at / U59230 / NM— 016743 I 29. nuc / NP— 058023 / 29. AA / - / D83018 I nel— related protein 2 nel-like 2 homolog (chicken) I 92358— at / U59230 / NM— 016743 I 29. nuc / NP— 058023 / 29. AA /-/ D83018 I nel— related protein 2
lysosomal— associated protein transmembrane 5 / 167764一 f一 at / AV3305ol / NM一 010686 I 30. nuc / NP— 034816 / 30. AA / Adra, C. N. et al, Genomics 35lysosomal— associated protein transmembrane 5/167764 1 f-1 at / AV3305ol / NM-1 010686 I 30. nuc / NP — 034816 / 30. AA / Adra, C. N. et al, Genomics 35
(2) , 328-337 (1996) / U51240 / lysosomal-associated multi transmembrane protein (LAPTm5) (2), 328-337 (1996) / U51240 / lysosomal-associated multi transmembrane protein (LAPTm5)
fibroblast growth factor binding protein 1 / 103995— at / AF065441 / NM一 008009 I 31. nuc I NP— 032035 / 31. AA / - / M60047 / heparin binding prot ein (HBpl7) FGF-BP1 fibroblast growth factor binding protein 1 / 103995— at / AF065441 / NM-1 008009 I 31. nuc I NP— 032035 / 31. AA /-/ M60047 / heparin binding prot ein (HBpl7) FGF-BP1
fibrinogen— like protein 2 / 97949— at / M16238 / NM一 008013 / 32. nuc I NP —032039 / 32. AA / Parr, R. L. et al, J. Virol. 69 (8) , 5033-5038 (1995) / Z36531 I fibrinogen- like 2 fibrinogen—like protein 2 / 97949—at / M16238 / NM-008013 / 32.nuc I NP —032039 / 32.AA / Parr, RL et al, J. Virol. 69 (8), 5033-5038 (1995) / Z36531 I fibrinogen- like 2
一データ 1 4 : One data 1 4:
(ヒトのアトピー性皮膚炎 （急性病変部と無疹部比較） と BALB/Cマウス接触性 膚炎モデル （ダニ感作耳介皮膚と非感作耳介皮膚比較） 間で共通変動 Z低下し た遺伝子群のマウス遺伝子）  (Common variation between human atopic dermatitis (compared to acute lesions and eruption) and BALB / C mouse contact dermatitis model (comparison of tick-sensitized and non-sensitized auricle skin) Mouse genes
keratin complex 1, acidic, gene 15 / 164618_f_at / AV171812 / NM— 008469 I 33. nuc I NP— 032495 I 33. AA / Nozaki, M. et al, Gene 138 (1—2) , 197-20keratin complex 1, acidic, gene 15 / 164618_f_at / AV171812 / NM— 008469 I 33. nuc I NP— 032495 I 33. AA / Nozaki, M. et al, Gene 138 (1-2), 197-20
0 (1994) I X07696 / cytokeratin 15 0 (1994) I X07696 / cytokeratin 15
sciellin Putative Ortholog I 161132— at / AA727482 I NM_022886 I 34. nucsciellin Putative Ortholog I 161132—at / AA727482 I NM_022886 I 34. nuc
1 NP— 075024 / 34. AA / Champliaud, M. F. et al, Genomics 70 (2) , 264-268 (2000) I AF045941 I sciellin (SCEL) protein tyrosine phosphatase, non-receptor type 21 / 99970一 at / D37801 I NM一 011877 I 35. nuc / NP一 036007 / 35. AA / Higashitsuji, H. et al, Oncog ene 10 (2) , 407-414 (1995) I X79510 / protein—tyrosine— phosphatase Dl expressed sequence AW494241 I 110469一 at / AW494241 /一 / 36· nuc /— /一1 NP— 075024 / 34. AA / Champliaud, MF et al, Genomics 70 (2), 264-268 (2000) I AF045941 I sciellin (SCEL) protein tyrosine phosphatase, non-receptor type 21 / 99970-1 at / D37801 I NM-1 011877 I 35.nuc / NP-1 036007 / 35.AA / Higashitsuji, H. et al, Oncogene 10 (2), 407-414 ( 1995) I X79510 / protein—tyrosine— phosphatase Dl expressed sequence AW494241 I 110469 at / AW494241 / one / 36nuc / — / one
I - I AB011109 I KIAA0537 I-I AB011109 I KIAA0537
apolipoprotein D / 93592— at / X82648 / Ml_007470 / 37. nuc / NP一 031496 /apolipoprotein D / 93592—at / X82648 / Ml_007470 / 37.nuc / NP-1 031496 /
37. AA I Yoshida, K. et al, DNA Cell Biol. 15 (10)， 873-882 (1996) / J026 11 / apolipoprotein D 37. AA I Yoshida, K. et al, DNA Cell Biol. 15 (10), 873-882 (1996) / J026 11 / apolipoprotein D
GATA binding protein 3 / 100924— at / X55123 / NM— 008091 / 38. nuc I NP— 0 32117 / 38. AA / Ko, L. J. et al, Mol. Cell. Biol. 11 (5)， 2778-2784 (199 1) I X58072 I GATA3  GATA binding protein 3 / 100924—at / X55123 / NM—008091 / 38.nuc I NP—0 32117 / 38.AA / Ko, LJ et al, Mol. Cell. Biol. 11 (5), 2778-2784 (199 1) I X58072 I GATA3
Id4 dominant negative helix-loop-helix gene / 96144一 at / AJ001972 I NM— 031166 / 39. nuc I NP— 112443 / 39. AA / Riechmann, V. et al, Nucleic Acid s Res. 22, 749-755 (1994) / AL022726 / Inhibitor of DNA binding 4 (ID4) RIKEN cDNA 4631434019 gene / 94801— at / AI607332 / - / 40. nuc / - / - / 一 I AJ002030 / progesterone receptor membrane component 2  Id4 dominant negative helix-loop-helix gene / 96144 at / AJ001972 I NM— 031166 / 39.nuc I NP—112443 / 39.AA / Riechmann, V. et al, Nucleic Acids Res. 22, 749-755 ( 1994) / AL022726 / Inhibitor of DNA binding 4 (ID4) RIKEN cDNA 4631434019 gene / 94801—at / AI607332 /-/ 40.nuc /-/-/ I I AJ002030 / progesterone receptor membrane component 2
CDCREL-1 homolog / 96337— at / AF033350 / - / 41. nuc / - / 41. AA / - / U 59b 2 I peanut-like 1 (Drosophila) CDCREL-1 homolog / 96337— at / AF033350 /-/ 41. nuc /-/ 41. AA /-/ U 59b 2 I peanut-like 1 (Drosophila)
adipocyte complement related protein of 30 kDa / 99,104— at / U49915 / NM 一 009605 I 42. nuc I NP— 033マ 35 / 42. AA I Hu, E. et al, J. Biol. Chem. 271 (18) , 10697 - 10703 (1996) I D45371 / apMl (adipose most abundant gene tra nscript 1) adipocyte complement related protein of 30 kDa / 99,104— at / U49915 / NM 1 009605 I 42. nuc I NP— 033 ma 35/42. AA I Hu, E. et al, J. Biol. Chem. 271 (18), 10697-10703 (1996) I D45371 / apMl (adipose most abundant gene transcript 1)
loricrin / 92624一 r一 at / U09189 I NM一 008508 I 43. nuc / NP— 032534 / 43. AA I Mehrel, T. et al, Cell 61 (6) , 1103 - 1112 (1990) / M63394 / loricrin cDNA, 5' end / 102225— at I AA163268 / - / 44. nuc / - / _ / - / AB007940 I KIAA0471 〔実施例 6〕 正常ヒト表皮角化細胞において IL-4、 IL-13 あるいは IFN - y刺 激により発現変動する遺伝子群とアトピー性皮膚炎患者の皮膚組織において発 現変動する遺伝子群の比較 loricrin / 92624-r at at / U09189 I NM-008508 I 43.nuc / NP-032534 / 43.AA A Mehrel, T. et al, Cell 61 (6), 1103-1112 (1990) / M63394 / loricrin cDNA , 5 'end / 102225—at I AA163268 /-/ 44.nuc /-/ _ /-/ AB007940 I KIAA0471 [Example 6] Comparison of genes that fluctuate in expression in normal human epidermal keratinocytes by IL-4, IL-13 or IFN-y stimulation and genes that fluctuate in skin tissue of atopic dermatitis patients
IL-4、 IL-13 および IFN-γはアトピー性皮膚炎の病態形成に重要なサイトカ インであり、 IL- 4および IL-13 はアトピー性皮膚炎患者の急性病変部において 無疹部に比べて発現が増加していること、 また IFN - yはアトピー性皮膚炎患者 無疹部において健常人の正常組織に比べて発現が低下していることが報告され ている。 我々は入手した患者および健常人の皮膚組織における IL- 4、 IL-13お ょぴ IFN- γの発現を定量的 PCRにて検討した。  IL-4, IL-13 and IFN-γ are important cytokines in the pathogenesis of atopic dermatitis, and IL-4 and IL-13 are more acutely affected in atopic dermatitis patients It has been reported that the expression of IFN-y is decreased in the non-rash area of patients with atopic dermatitis as compared with normal tissues of healthy persons. We examined the expression of IL-4, IL-13, and IFN-γ in the skin tissues of the obtained patients and healthy subjects by quantitative PCR.
(1) 定量的 PCR用の cDNA合成  (1) cDNA synthesis for quantitative PCR
皮膚検体から抽出した total RNAを DNase (二ツボンジーン)処理し、 oligo T), 2_18 (GIBCO BRL)をプライマーとして逆転写した cDNAを铸型とした。 同時に、 コ ピー数を算出する標準曲線のために両プライマーで増幅される塩基配列領域を 含むプラスミドクローンを各々の遺伝子について準備し、 その段階希釈を铸型 として反応を行つた。 定量的 PCRの反応液組成は表 8 3に示した。 Total RNA extracted from skin specimens was treated with DNase (Nitsubo Gene), and reverse transcribed cDNA using oligo T), 2 _ 18 (GIBCO BRL) as a primer was designated as type I. At the same time, a plasmid clone containing a nucleotide sequence region amplified by both primers was prepared for each gene for a standard curve for calculating the number of copies, and the reaction was carried out using the serial dilution as type III. Table 83 shows the composition of the reaction solution for quantitative PCR.
【表 8 3】  [Table 8 3]
ABI-PRISM 7700の反応組成 (1ゥヱルあたりの反応量）  Reaction composition of ABI-PRISM 7700 (reaction amount per liter)
23.75 (βΐ) 23.75 (βΐ)
10x Taq anバッファー A 5  10x Taq an buffer A 5
25mM MgCl2 7 25mM MgCl 2 7
dATP(lOmM) 1.0  dATP (lOmM) 1.0
dCTP (lOmM) 1.0  dCTP (lOmM) 1.0
dGTP (lOmM) 1.0  dGTP (lOmM) 1.0
dUTP (20mM) 1.0  dUTP (20mM) 1.0
Forward Primer (ΙΟμΜ) 1.0 Reverse Primer (10 ^M) 1.0 1 Forward Primer (ΙΟμΜ) 1.0 Reverse Primer (10 ^ M) 1.0 1
TaqManプローブ（2.0 μΜ) 2.5  TaqMan probe (2.0 μΜ) 2.5
AmpliTaq Gold (5U/^L) 0.25  AmpliTaq Gold (5U / ^ L) 0.25
AmpErase UNG (lU/^L) 0.5  AmpErase UNG (lU / ^ L) 0.5
テンプレート溶液 5  Template solution 5
50 50
(2) IL- 4、 IL- 13および IFN-γ遺伝子の皮膚組織における発現解析 (2) Expression analysis of IL-4, IL-13 and IFN-γ genes in skin tissue
IL-4、 IL- 13および IFN-γ遺伝子の皮膚組織における発現量を定量的に評価する ために、 ABI 7700 (Applied Biosystems)を用いて定量的 PCRを行った。 ABI 7700 による測定に用いたプライマーおよび TaqManプローブは、 各遺伝子の配列情報に 基づいて Primer Express (PEバイオシステムズ） により設計した。 使用した全て の TaqManプ口ーブの 5'末端は FAM (6- carboxy- fluorescein)で、 また 3，末端は TAMR A (6-carboxy-N, N， N' , ' -tetramethylrhodamine) で標識した。  In order to quantitatively evaluate the expression levels of IL-4, IL-13 and IFN-γ genes in skin tissues, quantitative PCR was performed using ABI 7700 (Applied Biosystems). Primers and TaqMan probes used for measurement with ABI 7700 were designed by Primer Express (PE Biosystems) based on the sequence information of each gene. The 5 'end of all TaqMan probes used was labeled with FAM (6-carboxy-fluorescein), and the 3' end was labeled with TAMR A (6-carboxy-N, N, N ',' -tetramethylrhodamine). .
また、 試料中の cDNA濃度の差を補正するため、 補正用内部標準として) 3-ァクチ ン（i3-actin)遺伝子、 およぴグリセルアルデヒド 3リン酸脱水素酵素 (GAPDH)遺伝 子について同様の定量解析を行い、 それら遺伝子のコピー数を基に補正して、 目 的遺伝子のコピー数を算出した。 各遺伝子のフォワードプライマー （F) 、 リバ —スプライマ一 （R) 、 および TaqManプローブ （TP) に用いたオリゴヌクレオ チドの塩基配列は、 以下に示すとおりである。 各指標遺伝子の塩基配列に対応す る Genbankのァクセッション番号を、 遺伝子名に続けて表示した。  The same applies to the 3-actin (i3-actin) gene and the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene to correct for differences in cDNA concentration in the sample. Quantitative analysis was performed, and the copy number of the target gene was calculated by correcting based on the copy number of those genes. The nucleotide sequences of the oligonucleotides used for the forward primer (F), reverse primer (R), and TaqMan probe (TP) for each gene are as shown below. The accession number of Genbank corresponding to the nucleotide sequence of each indicator gene is displayed following the gene name.
IL-4 (GenBank Acc.： NM_000589) IL-4 (GenBank Acc .: NM_000589)
F ： 5' -CACAGGCACAAGCAGCTGAT-3' (配列番号： 130)  F: 5'-CACAGGCACAAGCAGCTGAT-3 '(SEQ ID NO: 130)
R： 5' -CGCCAGGCCCCAGAG-3' (配列番号： 131)  R: 5'-CGCCAGGCCCCAGAG-3 '(SEQ ID NO: 131)
TP ： 5' -CGATTCCTGAAACGGCTCGACAGG-3' (配列番号： 132)
Figure imgf000315_0001
TP: 5'-CGATTCCTGAAACGGCTCGACAGG-3 '(SEQ ID NO: 132)
Figure imgf000315_0001
IL-13 (GenBank Acc.： NM一 002188)  IL-13 (GenBank Acc .: NM-00210021)
F ： 5， -ATCACCCAGAACCAGAAGGCT-3' (配列番号： 133)  F: 5, -ATCACCCAGAACCAGAAGGCT-3 '(SEQ ID NO: 133)
R： 5' -TACATGCCAGCTGTCAGGTTG-3' (配列番号： 134)  R: 5'-TACATGCCAGCTGTCAGGTTG-3 '(SEQ ID NO: 134)
TP ： 5' -TGCAATGGCAGCATGGTATGGAGC-3' (配列番号： 135) TP: 5'-TGCAATGGCAGCATGGTATGGAGC-3 '(SEQ ID NO: 135)
IFN-γ (GenBank Acc.： NM— 000619) IFN-γ (GenBank Acc .: NM—000619)
F： 5' -TCCAACGCAAAGCAATACATG-3' (配列番号： 136)  F: 5'-TCCAACGCAAAGCAATACATG-3 '(SEQ ID NO: 136)
R： 5， - CGCTTCCCTGTTTTAGCTGC- 3, (配列番号： 137)  R: 5,-CGCTTCCCTGTTTTAGCTGC- 3, (SEQ ID NO: 137)
TP： 5' -TCCAAGTGATGGCTGAACTGTCGCC-3' (配列番号： 138) TP: 5'-TCCAAGTGATGGCTGAACTGTCGCC-3 '(SEQ ID NO: 138)
GAPDHにより補正した各遺伝子の発現量 (copy/5ng total RNA) を図 1〜3に示 す。 図 1〜3に示すように、 我々が網羅的遺伝子発現解析に使用した検体におい ても複数の症例で、 IL- 4および IL- 13は患者無疹部に比べて皮疹部で高発現してお り、 IFN-yは患者無疹部に比べて健常人正常組織で、 また患者無疹部に比べて皮 疹部において高努現していることが確認された。  Figures 1-3 show the expression level (copy / 5ng total RNA) of each gene corrected by GAPDH. As shown in Figs. 1-3, in several of the samples we used for comprehensive gene expression analysis, IL-4 and IL-13 were more highly expressed in the eruption area than in the non-rash area in patients. In addition, it was confirmed that IFN-y exerted higher efforts in normal tissues of healthy subjects than in the non-rash area of the patient, and in the rash area of the patient compared to the non-rash area of the patient.
続いて、 ヒト表皮角化細胞 (ケラチノサイト) を IL- 4、 IL - 13あるいは IFN - γで 刺激を行い、 それぞれの刺激によりケラチノサイトで発現が変動する遺伝子を選 択し、 更にヒト皮膚組織を用いた網羅的発現解析結果との比較を行い、 共通変動 遺伝子の選択を行った。  Subsequently, human epidermal keratinocytes (keratinocytes) are stimulated with IL-4, IL-13, or IFN-γ, and genes whose expression fluctuates in keratinocytes by each stimulation are selected, and human skin tissue is used. The results were compared with the results of the comprehensive expression analysis, and a common variation gene was selected.
(3) ヒト表皮角化細胞 (ケラチノサイト) の IL-4、 IL - 13あるいは IFN-ッ刺激 市販の正常ヒト表皮角化細胞（Neonatal Normal Human Epidermal Keratinocyte s, pooled: NHEK-Neo Pooled (Bio WHITTAKER社)）を、 細胞密度が 3500細胞ん m2に なるようにフラスコ （底面積 75 cm2) に播種し、 15mL/フラスコの KGM SingleQuot s培地 (Bio WHITTAKER社)で培養を開始した。 播種した翌日に培地交換を行い、 そ れ以後 1日おきに培地交換をしながら培養を継続した。 細胞密度が 50%コンフレン ト以上になった時点 （播種後 6日目） で細胞をトリプシン処理により回収し、 6ゥ エルプレートに細胞密度 1〜2X105細胞/ゥエル、 培地量 2mL/ゥエルとなるように 継代した。 (3) Stimulation of human epidermal keratinocytes (keratinocytes) with IL-4, IL-13 or IFN-Neontal Normal Human Epidermal Keratinocytes, pooled: NHEK-Neo Pooled (Bio WHITTAKER )) Was seeded in a flask (bottom area: 75 cm 2 ) so that the cell density became 3500 cells m 2 , and culture was started in 15 mL / flask of KGM SingleQuots medium (Bio WHITTAKER). The medium was changed the day after seeding, and thereafter the culture was continued while changing the medium every other day. When the cell density reaches 50% confluence or more (6 days after seeding), the cells are collected by trypsinization, and the cell density in a 6-well plate is 1-2 x 10 5 cells / well, and the medium volume is 2 mL / well. like Passaged.
6ゥエルプレートに継代した翌日または翌々日に、 培地交換を行うとともに培養 系にそれぞれのサイトカインを加え （IFN (SIGMA社 cat. # 1-1520) ； 200U/mL、 IL-4 (PeproTechEC社 cat. #200-04) ； 10ng/mL、 IL-13 (PeproTechEC¾h cat. #20 0-13) ； 50ng/mL) 、 刺激培養を開始し、 以降経時的 （刺激後 6時間、 12時間、 24 時間、 48時間） にサンプリングを行った。 回収した細胞は RNA抽出用試薬 IS0GEN (二ツボンジーン社） lmL/ゥ工ルに溶解し、 - 80°Cにて保存した。  On the next day or two days after the passage into the 6-well plate, change the medium and add each cytokine to the culture system (IFN (SIGMA cat. # 1-1520); 200U / mL, IL-4 (PeproTechEC cat # 200-04); 10ng / mL, IL-13 (PeproTechEC¾h cat. # 200-13); 50ng / mL), start stimulating culture, and then elapse over time (6 hours, 12 hours, 24 hours after stimulation) , 48 hours). The recovered cells were lysed in lmL / volume of RNA extraction reagent IS0GEN (Futtsubon Gene) and stored at -80 ° C.
( 4 ) 遺伝子発現解析用 total. RNAの調製  (4) Preparation of total RNA for gene expression analysis
サイトカイン刺激後の細胞を Isogen試薬に溶解し、 以降はそのマニュアルに従 つて total RNAの調製を行った。 細胞溶解液にクロ口ホルムを加え、 攪拌遠心して 水層を回収した。 次にイソプロパノールを加え、 攪拌遠心して沈殿を回収した。 沈殿は 75%エタノールでリンス、 遠心を行い、 沈殿を total RNAとして回収した。  Cells after cytokine stimulation were lysed in Isogen reagent, and then total RNA was prepared according to the manual. A black-mouthed form was added to the cell lysate, and the mixture was centrifuged with stirring to collect an aqueous layer. Next, isopropanol was added, and the mixture was stirred and centrifuged to collect the precipitate. The precipitate was rinsed with 75% ethanol and centrifuged, and the precipitate was collected as total RNA.
( 5 ) ジーンチップ解析用の cDNA、 cR Aの合成  (5) Synthesis of cDNA and cDNA for gene chip analysis
Total RNA 2— 5 ^ g力 ら、 T7 -（dT) 24 (Amersham Pharmacia Biotech)をプライマー として、 Affymetrix社の Expression Analysis Technical Manualに従レヽ、 Supersc ript II Reverse Transcriptase (Life Technologies社)を用レヽて逆転 し、 1本 鎖 cDNAを作製した。 Total RNA 2-5 ^ g, T7-(dT) 24 (Amersham Pharmacia Biotech) as primer, according to Affymetrix Expression Analysis Technical Manual, Superscript II Reverse Transcriptase (Life Technologies) This was reversed to produce a single-stranded cDNA.
Γ7- (dT) 24プライマーは、 以下のように T7プロモーターの塩基配列に (dT)24を付 加した塩基配列からなる。 Γ7- (dT) 24 primer consists of a nucleotide sequence obtained by adding (dT) 24 to the nucleotide sequence of the T7 promoter as follows.
T7 -（dT) 24プライマー： 5' -GGCCAGTGAATTGTAATACGACTCACTATAGGGAGGCGG- (dT) M-3 ' (配列番号： 4 7 ) T7- (dT) 24 primer: 5'-GGCCAGTGAATTGTAATACGACTCACTATAGGGAGGCGG- (dT) M- 3 '(SEQ ID NO: 47)
次に、 DNA Ligase, DNA polymerase Iおよび RNase Hを加え、 2本鎖 cDNAを合成 した。 cDNAをフエノール'クロ口ホルム抽出後、 Phase Lock Gelsに供し、 ェタノ ール沈殿により精製した。  Next, DNA Ligase, DNA polymerase I and RNase H were added to synthesize a double-stranded cDNA. After extracting the cDNA with phenol-cloth form, the cDNA was subjected to Phase Lock Gels and purified by ethanol precipitation.
さらに、 BioArray High Yield RNA Transcription Labeling Kitを用い、 ピオ チンラベルした cRNAを合成した。 合成した cRNAは RNeasy Spin column (QIAGEN)を 用いて精製を行い、 アル力リ処理により断片化を行つた。 Furthermore, using the BioArray High Yield RNA Transcription Labeling Kit, biotin-labeled cRNA was synthesized. For the synthesized cRNA, use the RNeasy Spin column (QIAGEN). Purification was carried out and fragmentation was carried out by a complete treatment.
( 6 ) GeneChipを用いた遺伝子発現解析  (6) Gene expression analysis using GeneChip
Expression Analysis Technical Manual (Affymetrix)に従レヽ、 斬片化した cRNA (10 /i g)を用いてハイプリダイゼーションカクテノレを作製し、 これをチップに入れ て 45°Cで 16時間ハイプリダイゼーシヨンさせた。 チップには GeneChip00 Human Ge nome U95Av2 (Affymetrix社）を用いた。 ハイブリダィズした後にチップを洗浄し、 Streptavidin - Phycoerythrinを加えて染色した。 洗浄後、 normal ャギ IgGとビォ チン化ャギ抗ストレプトアビジン IgG抗体の混合液をァレイに加えて反応させた。 更に、 蛍光強度を増強する目的で、 再度 Streptavidin- Phycoerythrinを加え染色 した。 洗浄後、 チップをスキャナーにセットして蛍光強度を読み取った。 According to the Expression Analysis Technical Manual (Affymetrix), prepare a hybridization primer using fragmented cRNA (10 / ig), insert it into a chip, and allow it to hybridize at 45 ° C for 16 hours. Was. GeneChip 00 Human Genome U95Av2 (Affymetrix) was used for the chip. After hybridization, the chip was washed and stained with Streptavidin-Phycoerythrin. After washing, a mixture of normal goat IgG and biotinylated goat anti-streptavidin IgG antibody was added to the array and reacted. Furthermore, for the purpose of enhancing the fluorescence intensity, Streptavidin-Phycoerythrin was added again for staining. After washing, the chip was set on a scanner and the fluorescence intensity was read.
読み取つた蛍光強度は、 DNAチップ解析ソフトである Suite4. 0を用いてデータの 解析を行った。 データの解析は GeneChip Analysis Suite User Guideに従って行 つた。  The read fluorescence intensity was analyzed for data using Suite 4.0, a DNA chip analysis software. Data analysis was performed according to the GeneChip Analysis Suite User Guide.
まず全てのチップについて Absolute analysisを行い、 用いたサンプル各々の遺 伝子発現量を測定した。 また、 全ての transcriptに対して、 それぞれのプローブ セットのパーフエクトマツチとミスマッチの蛍光強度を比較し、 Absolute Callで ある P (present) , A (absent)およ （marginal)の 3区分の判定を行った。  First, Absolute analysis was performed for all chips, and the gene expression level of each sample used was measured. In addition, for all transcripts, the fluorescence intensity of the mismatch between the perfect match and the mismatch of each probe set was compared, and the three categories of P (present), A (absent) and (marginal), which are the absolute calls, were determined. went.
サンプル間 （チップ間） の遺伝子発現を比較する場合には Comparison analysis を行った。 チップ間の補正は、 各チップの全プローブセットの蛍光強度平均値が 一定になるように捕正を行った。  Comparison analysis was performed to compare gene expression between samples (between chips). Correction between chips was performed so that the average fluorescence intensity of all probe sets of each chip was constant.
IL - 4、 IL- 13あるいは IFN - γ刺激によりケラチノサイトにおいて変動する遺伝子群 とアトピー性皮膚炎患者の皮膚組織で変動する遺伝子群との比較  Comparison of genes fluctuating in keratinocytes by IL-4, IL-13 or IFN-γ stimulation with genes fluctuating in skin tissue of patients with atopic dermatitis
それぞれの刺激を加えて 48時間後のケラチノサイトにおける遺伝子発現と刺激 を加えずに 48時間培養したケラチノサイトの遺伝子発現を Comparison analysisに より比較解析を行い、 各刺激により発現変動する遺伝子のリストを作成した。 そ のリストをアトピ一性皮膚炎患者の無疹部と皮疹部間で変動する遺伝子群と比較
Figure imgf000318_0001
The gene expression in keratinocytes 48 hours after applying each stimulus and the gene expression of keratinocytes cultured for 48 hours without stimulus were compared and analyzed by Comparison analysis, and a list of genes whose expression fluctuated due to each stimulus was created. . Compare the list with the genes that fluctuate between the eruption and the eruption in atopic dermatitis patients
Figure imgf000318_0001
を行った結果を表 8 4〜表 9 4に、 健常人の正常組織とアトピー性皮膚炎患者の 無疹部間で変動する遺伝子群と比較した結果を表 9 5〜表 1 0 2に示した。 Tables 84 to 94 show the results of the comparison, and Table 95 to Table 102 show the results of comparisons between the normal tissues of healthy subjects and the genes that fluctuate between the eruptions of atopic dermatitis patients. Was.
IL-4、 IL- 13および IFN- yは実際にァトピー性皮膚炎患者の皮膚組織において発 現変動が認められていることから、 これらのサイトカインが表皮ケラチノサイト に作用して患者皮膚組織における遺伝子発現プロファイルに影響を及ぼしている 可能性は充分考えられる。 実際、 患者皮膚組織におけるこれらサイト力インのプ 口ファイルと矛盾すること無く、 サイトカイン刺激ケラチノサイトと患者皮膚組 織で共通変動する遺伝子が数多く見出された。 このような解析は患者皮膚組織で 変動している他のサイトカインを用いて同様に行うことができ、 AD病態関連遺伝 子の発現を誘導あるいは抑制可能な因子を推測することができる。  Since IL-4, IL-13 and IFN-y have actually been altered in the expression of skin tissue in patients with atopic dermatitis, these cytokines act on epidermal keratinocytes and cause gene expression in the patient's skin tissue It is quite possible that it is affecting the profile. Indeed, a number of commonly fluctuating genes were found in cytokine-stimulated keratinocytes and in patient skin tissue, consistent with these site-involved mouth files in patient skin tissue. Such an analysis can be similarly performed using other cytokines fluctuating in the patient's skin tissue, and a factor capable of inducing or suppressing the expression of an AD pathology-related gene can be estimated.
表 8 4  Table 8 4
ァトピー性皮膚炎患者の無疹部と皮疹部間の比較で、 皮疹部で発現が増加して いた遺伝子 （表 2〜表 5 ) とサイト力イン刺激ケラチノサイトと無刺激ケラチノ サイト間で発現が変動した遺伝子を比較した結果を示した。 表中に記載されてい る、 ΐ ΐ ††は変動が 50倍以上、 † † †は 10〜50倍、 † Tは 3〜10倍、 †は 2〜3倍、 一は変動なし、 丄丄丄丄は 1/50倍以下、 丄丄丄は 1/50〜； 1/10倍、 丄丄は 1/10〜； 1/3 倍、 丄は 1/3〜： 1/2倍であることを示す。 In the comparison between non-rash and rash areas in patients with atopic dermatitis, genes whose expression was increased in the rash area (Tables 2 to 5) and the expression fluctuated between stimulating keratinocytes and non-stimulating keratinocytes The results of comparing the obtained genes are shown. In the table, 変 動 ΐ 変 動 has a variation of 50 times or more, † † 10 10 to 50 times, † T 3 to 10 times, † 2 to 3 times, one has no change, は丄 丄 is 1/50 times or less, 丄 丄 丄 is 1/50 ~; 1/10 times, 丄 丄 is 1/10 ~; 1/3 times, 丄 is 1/3 ~: 1/2 times Is shown.
ΤΤΤί 50倍以上 1/50倍以下 ΤΤΤί 50 times or more 1/50 times or less
TTT 10-50倍 •l"J"l 1/50~1/10倍 3-10倍 u 1/10〜 3倍 2-3倍 1/3~1/2倍 変動なし  TTT 10-50 timesl "J" l 1 / 50-1 / 10 times 3-10 times u 1 / 10-3 times 2-3 times 1 / 3-1 / 2 times No change
^ I ^ I
I I
Figure imgf000319_0001
Figure imgf000319_0001
Chemokine, Chemokine receptor Chemokine, Chemokine receptor
34375 at ίΐ ίΐ †T ίί ί ίί ΤΤ1 ίΤΤ 28225  34375 at ίΐ ίΐ † T ίί ί ίί ΤΤ1 ίΤΤ 28225
875 g at ττ Τί Τί Τί τ ττ ΤΤ1 ΤΤί Μ26683  875 g at ττ Τί Τί τ τ ττ ΤΤ1 ΤΤί Μ26683
37187一 at ττ ίί ίί ίί ί ί ίί ίί ί ίίί Μ36820  37187 i at ττ ίί ίί ίί ί ί ίί ίί ί Μ 2036820
408 at ίί ίί ίί ίΐ ίί ττ π ίΤ Χ54489  408 at ίί ίί ίί ίΐ ίί ττ π ίΤ Χ54489
SI 00 family proteins ( smalI(10-14kDa) calcium binding protein )  SI 00 family proteins (smalI (10-14kDa) calcium binding protein)
41471— at I†i† I ΤΤί ίίΤί TTT ί I Τί I TT Ι ίίίί †TT ΤΤίίΙ ίίί - - ΐ 1 1 - W72424  41471—at I † i † I ΤΤί ίίΤί TTT ί I Τί I TT Ι ίίίί † TT ΤΤίίΙ ίίί--ΐ 1 1-W72424
Cell adhesion and Related molecule  Cell adhesion and Related molecule
1372 at - 一 τ τ . τ ι π - - - ττί ίί - - Πί - - - Μ31165  1372 at-one τ τ. Τ ι π---ττί ίί--Πί---Μ31165
CD antigen, Immunoglobulin- ike receptor  CD antigen, Immunoglobulin- ike receptor
37890 at ί ίί τ τ ττ ττ ίί τ ττ Χ69398  37890 at ίί τ τ τ ττ ττ ίί τ ττ Χ69398
37148— at Τί η ίΤ Τί τ ίίί τ τ AF025533  37148—at η η ίΤ τ τ ίίί τ τ AF025533
Extracellular matrix protein  Extracellular matrix protein
32818 at †T ίί Τί ίΤ Τί ί †T I ίί ίΤ ΤΤί I Τί m 1 ίίί ΪΤ - - Χ78565  32818 at † T ίί Τί ίΤ Τί ί IT I ίί ίΤ ΤΤί I Τί m 1 ίίί ΪΤ--Χ78565
Kinase and Phosphatase  Kinase and Phosphatase
1402 at ί ί T† t ί ίί ίί ί ΐί Μ16038  1402 at ί ί T † t ί ίί ίί ί ΐί 3816038
677— s一 at Τ ττ ίί ί τ ττ ττ Τί J04430  677— s-at at τ ττ ίί ί τ ττ ττ Τί J04430
Enzyme ( without protease, kinase, phosphatase )  Enzyme (without protease, kinase, phosphatase)
32775 r at ί ίί ί ΐ ίί τ ίί ΑΒ006746  32775 r at ί ίί ί ΐ τ τ ίί ΑΒ006746
34666 at Τί ίί Τί ΐί ίΤ ί τττ TT† τττ Χ07834  34666 at Τί ίί Τί ΐί ίΤ ί τττ TT † τττ Χ07834
36203 at †T ί ίΤ τ ίί Τί τ 11 Χ16277  36203 at † T ί τ τ ίί τ τ 11 Χ16277
37032 at † Τί ίΤ ί τ ττ Τί ττ U08021  37032 at † Τί ίΤ ί τ ττ Τί ττ U08021
37351 at m ΐΐί Τΐί ττ ΐΐί ΐΐί ΐΐί ίΠ Τί ί ί Χ90858  37351 at m ΐΐί Τΐί ττ ΐΐί ΐΐί ΐΐί ίΠ Τί ί ί 85890858
38389 at ίΐ τ ί ί τ ττ τ ττ ϊ Χ04371  38389 at τ τ ί ί τ ττ τ ττ ϊ Χ04371
39263 at †T ίΐ † ί τ η τ Τί I Μ87434  39263 at † T ίΐ † τ τ η τ Τί I Μ87434
34491 at T† ίί ί ίί ί ίΐ ίί m AJ225089  34491 at T † ίί ί ίί ίί ίΐ ίΐ m AJ225089
^ ^8 ^ ^ 8
^ 31
Figure imgf000321_0001
^ 31
Figure imgf000321_0001
6 6
0 32 表 8 7 0 32 Table 8 7
アトピー性皮膚炎患者の無疹部と皮疹部間の比較で、 皮疹部で努現が増加して いた遺伝子 （表 2〜表 5 ) とサイト力イン刺激ケラチノサイトと無刺激ケラチノ サイト間で発現が変動した遺伝子 （表 8 4〜表 8 6 ) の説明を示した。 In the comparison between the non-rash area and the rash area in patients with atopic dermatitis, the genes whose efforts were increased in the rash area (Tables 2 to 5) and the expression between the stimulating keratinocytes and the unstimulated keratinocytes were observed. Explanations of the fluctuated genes (Table 84 to Table 86) are shown.
表 J-1 (D) :ヒト AD症例由来遺伝子（皮疹部で発現上昇遺伝子/無疹部比）とケラチノサイト刺激実験 (IL-4、 IL - 13、 IFN- γ ) 由来遺伝子の比較 Table J-1 (D): Comparison of genes derived from human AD cases (increased expression ratio in the rash area / apparent area ratio) and keratinocyte stimulation experiments (IL-4, IL-13, IFN-γ)
Increase  Increase
Figure imgf000323_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000325_0001
40297 at AC005053 six transmembrane epithelial antigen of the prostate (STEAP) 40297 at AC005053 six transmembrane epithelial antigen of the prostate (STEAP)
表 9 0 Table 90
アトピー性皮膚炎患者の無疹部と皮疹部間の比較で、 皮疹部で発現が減少して いた遺伝子 （表 6〜表 9 ) とサイト力イン刺激ケラチノサイトと無刺激ケラチノ サイト間で発現が変動した遺伝子を比較した結果を示した。 表中に記載されてい る、 † † † †は変動が 50倍以上、 す す ま10〜50倍、 † †は 3〜： 10倍、 †は 2〜3倍、 一は変動なし、 丄 丄 丄 丄は 1/50倍以下、 丄 丄 丄は 1/50〜： 1/10倍、 丄 丄は 1/10〜： 1/3 倍、 丄は 1/3〜1/2倍であることを示す。 In the atopic dermatitis patients, the expression decreased in the rash area (Tables 6 to 9) and the expression was fluctuated between the stimulating keratinocytes and non-stimulating keratinocytes The results of comparing the obtained genes are shown.変 動 † † 変 動 変 動 、 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動 変 動丄 丄 is 1/50 or less, 丄 丄 1 is 1/50 ~: 1/10 times, 丄 丄 is 1/10 ~: 1/3 times, 丄 is 1/3 ~ 1/2 times Show.
TTTT 1/50倍以下 TTTT 1/50 times or less
1/50〜1/10倍 1 / 50-1 / 10
TT u 1/10〜1/3倍 TT u 1/10 to 1/3 times
1/3〜1/2倍  1/3 to 1/2 times
t t
3 522 ^ 1 3 522 ^ 1
?¾動倍？ s.  ? ¾ s.
きな¾倍 3  Kinako times 3
Figure imgf000327_0001
Figure imgf000327_0001
CO CO
Figure imgf000328_0001
Figure imgf000328_0001
¾ 19 ¾ 19
35669 at i il u u i u u u T AB014533 0035669 at i il u u i u u u T AB014533 00
39625 at i u u l i I u AL050204 39625 at i u u l i I u AL050204
41679 at a i 11 u il u u AF035282  41679 at a i 11 u il u u AF035282
2 W Two W
3 2 9 ；' 3 2 9; '
表 9 3  Table 9 3
アトピー性皮膚炎患者の無疹部と皮瘆部間の比較で、 皮疹部で榮現が減少して いた遺伝子 （表 6〜表 9 ) とサイト力イン刺激ケラチノサイトと無刺激ケラチノ サイト間で発現が変動した遺伝子 （表 9 0〜表 9 2 ) の説明を示した。 In the atopic dermatitis patients, a gene whose expression was decreased in the rash area (Table 6 to Table 9) and a gene expression between the stimulating keratinocytes and non-stimulating keratinocytes The explanation of the genes (Tables 90 to 92) in which fluctuated was shown.
表 J -2 (D) :ヒト AD症例由来遺伝子（皮疹部で発現低下遺伝子/無疹部比）とケラチノサイト刺激実験 (IL-4、 IL-13. IFN- r ) 由来遺伝子の比較 Table J- 2 (D): Comparison of genes derived from human AD cases (expressed genes in the rash area / no rash area) and keratinocyte stimulation experiments (IL-4, IL-13. IFN-r)
Decrease  Decrease
Probe ID accession Descriptions  Probe ID accession Descriptions
Protease  Protease
40717 at AB001928 lcathepsin V  40717 at AB001928 lcathepsin V
Protease inhibitor  Protease inhibitor
33128 s at W68521 cystatin E/M  33128 s at W68521 cystatin E / M
35577 at AF027866 SERPINB7 (serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 7)  35577 at AF027866 SERPINB7 (serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 7)
Cell adhesion and related molecule  Cell adhesion and related molecule
37857 at AL080188 KIAA1775 ( MT-protocadherin)  37857 at AL080188 KIAA1775 (MT-protocadherin)
Cytoskeletal structura protein, cytoskeleton associated protein ω Cytoskeletal structura protein, cytoskeleton associated protein ω
37582 at X07696 cytokeratin 15 CO37582 at X07696 cytokeratin 15 CO
40899 at Y00503 keratin 19 〇40899 at Y00503 keratin 19 〇
39544 at AB002351 KIAA0353 / desmuslin (intermediate filament protein) 39544 at AB002351 KIAA0353 / desmuslin (intermediate filament protein)
Extracellular matrix protein  Extracellular matrix protein
39673 i at AB01 1792 extracellular matrix protein 2  39673 i at AB01 1792 extracellular matrix protein 2
Kinase and Phosphatase  Kinase and Phosphatase
33787一 at |AB01 1 109 IKIAA0537  33787 ichi at | AB01 1 109 IKIAA0537
Enzyme (without protease, kinase, phosphatase and alcohol dehydrogenase)  Enzyme (without protease, kinase, phosphatase and alcohol dehydrogenase)
32664 at D37931 RNase 4  32664 at D37931 RNase 4
36680 at M24895 amylase, alpha 2B; pancreatic  36680 at M24895 amylase, alpha 2B; pancreatic
37124 i at J04813 Cytochrome P450, subfamily IIIA, polypeptide 5  37124 i at J04813 Cytochrome P450, subfamily IIIA, polypeptide 5
37125 f at J04813 Cytochrome P450, subfamily IIIA, polypeptide 5  37125 f at J04813 Cytochrome P450, subfamily IIIA, polypeptide 5
Fatty acid metabolism related molecule  Fatty acid metabolism related molecule
33337 at AF002668 degenerative spermatocyte homolog ( sphingolipid delta 4 desaturase )  33337 at AF002668 degenerative spermatocyte homolog (sphingolipid delta 4 desaturase)
35185 at AJ002962 FABP7 ( fatty acid binding protein 7) 35185 at AJ002962 FABP7 (fatty acid binding protein 7)
Figure imgf000332_0001
Figure imgf000332_0001
6挲  6 挲
¾ ε ε  ¾ ε ε
808600/C00Zdf/X3d 98$：丽 OZ OAV 表 9 5 808600 / C00Zdf / X3d 98 $: 丽 OZ OAV Table 9 5
ァトピー性皮膚炎患者の無疹部と健常人の正常組織間の比較で、 ァトピー性皮 膚炎患者の無疹部で発現が増加していた遺伝子 （表 1 0〜表 1 2およぴ表 2 1 ) とサイトカイン刺激ケラチノサイトと無刺激ケラチノサイト間で発現が変動した 遺伝子を比較した結果を示した。 表中に記載されている、 † †† †は変動が 50倍 以上、 ΐ† †は 10〜50倍、 ††は 3〜10倍、 †は 2〜3倍、 一は変動なし、 丄丄 丄 丄 は 1/50倍以下、 丄 i 1は 1/50〜； 1/10倍、 1 iは 1/10〜1/3倍、 |は 1/3〜1/2倍であ ることを示す。 Genes whose expression was increased in the rash-free area of patients with atopic dermatitis (Tables 10 to 12 and Table 12) were compared between the rash-free area of patients with atopic dermatitis and the normal tissues of healthy subjects. 21) and the results of comparing genes whose expression fluctuated between cytokine-stimulated keratinocytes and unstimulated keratinocytes were shown. In the table, 変 動 †† 変 動 has a variation of 50 times or more, ΐ † 10 10 to 50 times, †† 3 to 10 times, † 2 to 3 times, one has no change, 変 動丄 丄 is less than 1/50 times, 丄 i 1 is 1/50 or more; 1/10 times, 1 i is 1/10 to 1/3 times, | is 1/3 to 1/2 times Show.
50倍以上 丄丄 丄 1/50倍以下 50 times or more 丄 丄 丄 1/50 times or less
TTT 10-50倍 1/50~1/10倍 TTT 10-50 times 1 / 50-1 / 10 times
Τί 3-10倍 U 1/10~1/3倍 2-3倍 1/3〜1/2倍 変動なし Τί 3-10 times U 1/10 ~ 1/3 times 2-3 times 1/3 ~ 1/2 times No change
1 1
Figure imgf000334_0001
Figure imgf000334_0001
36108 at ίί ίί ίί ίίί ίί ίί - ίίί 一 Πί - Μ16276 36108 at ίί ίί ίί ίίί ίίί ίί-ίίί Πί Πί-Μ16276
G - protein and related molecule G-protein and related molecule
1876 at t ίί ί ί ί ί ί ίί 一 一  1876 at t ίί ί ί ί ί ί 一 一
I ranscriptional regulator protein '  I ranscriptional regulator protein ''
32064 at ί ίί ί ΐί ίΐ ίί ίί ίΤ ί Υ13467  32064 at ί ίί ί ί ΐί ίί ίί ίΤ Υ 6713467
40412 at す† ίί ίί ίί ί! ί it Ιί U ΑΑ203476 CO 40412 at † † ίί ίί ίί ί! Ί it Ιί U ΑΑ203476 CO
1952 s at ί Τί η Τί ίί ίί ίί ί i AF010607 CO 1952 s at ί η η Τί ίί ίί ίί AF i AF010607 CO
Cell cycle relatec molecule Cell cycle relatec molecule
38326 at † ίί ίί ίί Πί ίί † すす Μ69199  38326 at † ίί ίί ίί Πί ίί † Soot Μ69199
1945 at ί ίί ί ίί ί ί ίί ίί ί U Μ25753  1945 at ί ίί ί ίί ί ί ίί ίί ίί ί U Μ25753
Others  Others
38116 at ίί ίす ir ίί ί Τί ίί ΐί ί ϊ ί U 陽 57  38116 at ίί ί ί ί ί ί ϊ ί 陽 U Yang 57
40478 at ίί ΐί π ίί ίί ΐί ίί ίί ίί ϊ u AL021396  40478 at ΐί π π ίί ίί ΐί ίί ίί ϊ AL u AL021396
41870 at it ίす Τί Τί ίί ΐΐ ίί ίί ίί AF030428  41870 at it ί ί Τί Τί Τί ίί ΐΐ ίί ίί ίί 030 AF030428
521 at ίίί Τί τ ίί ίίί ίΐ ίί Πί ίί a U07807  521 at Τί τ τ ίί ίίί ίΐ ίί Πί ίί a U07807
40354— at † 1 † ί ίί ί † u AB023421  40354—at † 1 ί ί ίί ί † u AB023421
^96 表 9 7 ^ 96 Table 9 7
ァトピー性皮膚炎患者の無疹部と健常人の正常組織間の比較で、 ァトピー性皮 膚炎患者の無疹部で発現が増カ卩していた遺伝子 （表 1 0〜表 1 2および表 2 1 ) とサイトカイン刺激ケラチノサイトと無刺激ケラチノサイト間で発現が変動した 遺伝子 （表 9 5〜表 9 6 ) の説明を示した。 In the comparison between the non-rash area of atopic dermatitis patients and the normal tissue of healthy subjects, the genes whose expression was increased in the non-rash area of patients with atopic dermatitis (Tables 10 to 12 and Table 12) 21) and a description of the genes whose expression fluctuated between cytokine-stimulated keratinocytes and unstimulated keratinocytes (Tables 95-96) are shown.
Figure imgf000337_0001
Figure imgf000337_0001
40412 at AA203476 pituitary tumor-transforming protein 1 40412 at AA203476 pituitary tumor-transforming protein 1
Figure imgf000338_0001
Figure imgf000338_0001
表 9 9 Table 9 9
ァトピー性皮膚炎患者の無疹部と健常人の正常組織間の比較で、 ァトピー性皮 膚炎患者の無疹部で発現が減少していた遺伝子 （表 1 3〜表 1 5およぴ表 2 2〜 表 2 4 ) とサイトカイン刺激ケラチノサイトと無刺激ケラチノサイト間で楽現が 変動した遺伝子を比較した結果を示した。 表中に記載されている、 †† † †は変 動が 50倍以上、 1^ ま10〜50倍、 卞 卞は3〜10倍、 †は 2〜3倍、 一は変動なし、 I i 1 1は 1/50倍以下、 丄 は 1/50〜1/10倍、 I 1は 1/10〜： 1/3倍、 Iは 1/3〜1 /2倍であることを示す。 Genes whose expression was decreased in the eruption area of atopic dermatitis patients were compared between the eruption areas of atopic dermatitis patients and normal tissues of healthy subjects (Tables 13 to 15 and Table 15). 22 to Table 24) and the results of comparison of genes whose lucidity varied between cytokine-stimulated keratinocytes and unstimulated keratinocytes were shown. In the table, †† † † indicates that the fluctuation is 50 times or more, 1 ^ to 10 to 50 times, Byeon Byeon is 3 to 10 times, † is 2 to 3 times, one is no change, I i 1 1 is 1/50 or less, 丄 is 1/50 to 1/10, I 1 is 1/10 to: 1/3, and I is 1/3 to 1/2.
ΤΤίί 50倍以上 1/50倍以下 ΤΤίί 50 times or more 1/50 times or less
ίίί 10-50倍 1/50〜1/10倍  ίίί 10-50 times 1 / 50-1 / 10 times
ττ 3- 10倍 1/10〜1/3倍  ττ 3-10 times 1/10-1/3 times
2-3倍 1/3~1/2倍  2-3 times 1/3 ~ 1/2 times
変動なし  No change
表 K- 2 :ヒト症例由来遺伝子 (AD患者無疹部で発現低下遺伝子/健常人正常皮膚比)とケラチノサイト刺激実験 Table K-2: Genes derived from human cases (expressed genes in the rash of AD patients / normal skin ratio in healthy subjects) and keratinocyte stimulation experiments
(IL-4, 1し- 13、 IFN- γ )由来遺伝子の比較  Comparison of genes derived from (IL-4, 1-13, IFN-γ)
AD患者無疹部 <健常人正常組織  Eruption part of AD patient <Normal tissue of healthy person
ヒ卜症例 ケラチノサイト  Human case keratinocytes
Decrease Increase Human  Decrease Increase Human
Probe ID 2 3 4 6 , 9 10 11 12 13 15 16 17 IL-4 〖し _13【FN- IL-4 I IL-13【FN Accession franscnptional regulator protein  Probe ID 2 3 4 6, 9 10 11 12 13 15 16 17 IL-4 _13 [FN- IL-4 I IL-13 [FN Accession franscnptional regulator protein
1915 s at u a u Ui "i Ui ill Ui i u Ui u V01512 1915 s at u a u Ui "i Ui ill Ui i u Ui u V01512
1916 s at u u i iU ill u ii i u *i J"! V01512 CO1916 s at u u i iU ill u ii i u * i J "! V01512 CO
287 at in III u 1U 111 Hi Ui 丄丄丄 ii Ui i T T O 287 at in III u 1U 111 Hi Ui 丄 丄 丄 ii Ui i T T O
I ii し 19871 I ii then 19871
36214 at 1 i u u u u u Ϊ i ii T U70663 CD36214 at 1 i u u u u u Ϊ i ii T U70663 CD
1461— at I i a i Ϊ i i i i u ί M690431461—at I i a i Ϊ i i i i u ί M69043
36617 at n u u u u ΪΪ u u ΐ X7795636617 at n u u u u ΪΪ u u ΐ X77956
36618_g— at a a i li i u u u u ίί X7795636618_g—at a a i li i u u u u ίί X77956
36619 r at u iU i u J* J- J* u a I u ίΤΤ S7882536619 r at u iU i u J * J- J * u a I u ίΤΤ S78825
37043 at 1 1 Ϊ i i i i i I i u T T AL021 15437043 at 1 1 Ϊ i i i i i I i u T T AL021 154
Enzyme Enzyme
1069 at Ϊ Ϊ u i I i 1 Ϊ T † ττ U04636 1069 at Ϊ Ϊ u i I i 1 Ϊ T † ττ U04636
39372 at ill Ui m 1 u u Hi "1· Ί· J- i i W2648039372 at ill Ui m 1 u u Hi "1 · J-i i W26480
32190 at J- 1* Ί· Hi uu i 1 u Ui Hi J- "!* -i" u 1 u 11 AL05011832190 at J- 1 * Ί Hi uu i 1 u Ui Hi J- "! * -I" u 1 u 11 AL050118
35192 at u a u u u u u u Πί D9023935192 at u a u u u u u u Πί D90239
36203 at i i i i 11 i i i u u X1627736203 at i i i i 11 i i i u u X16277
37028 at I i 1 a il 1 1 i i T † U8398137028 at I i 1 a il 1 1 i i T † U83981
Gyclin - dependent kinase inhibitor Gyclin-dependent kinase inhibitor
1787 at u u Ϊ i u Ϊ i u 1 u U22398 1787 at u u Ϊ i u Ϊ i u 1 u U22398
38673 s at u u 1 li 1 i ii i u D64137 38673 s at uu 1 li 1 i ii iu D64137
CD antigen CD antigen
32640 at 11 u 1 I u I I u 1 Π ίίίί 24283  32640 at 11 u 1 I u I I u 1 Π ίίίί 24283
37536_at 11 u ii 11 il ii 1 I ί Ζ11697  37536_at 11 u ii 11 il ii 1 I ί Ζ11697
37645 at 1 I u i i Ϊ I Ϊ u † Ζ22576  37645 at 1 I u i i Ϊ I Ϊ u † Ζ22576
1083_s_at ΪΪ ΪΪ u i i u 11 I I ίί Μ35093  1083_s_at ΪΪ ΪΪ u i i u 11 I I ίί Μ 35093
Chemokine Chemokine
37187 at U 11 II U 1 U ii u ii u - u u - - - ΐ ίΤί 36820  37187 at U 11 II U 1 U ii u ii u-u u---ΐ ίΤί 36820
CO  CO
Growth factor 〇 Growth factor 〇
38037 at Ul 1 u ui Ul u i" i* i i iJ" u ii 一 ί Μ60278 38037 at Ul 1 u ui Ul u i "i * i i iJ" u ii ί 27860278
Others Others
35878 at 11 u 11 II il 11 ΪΪ u u u u 1 I ΑΒ023141  35878 at 11 u 11 II il 11 ΪΪ u u u u 1 I ΑΒ023141
39081 at 1 u I il 1 u u i 1 1 I u I i Α 47258  39081 at 1 u I il 1 u u i 1 1 I u I i Α 47258
41048 at 11 u 11 ii u 11 i u ί ί ίί D90070  41048 at 11 u 11 ii u 11 i u ί ί ίί D90070
35185 at -I *1* Ί Ί •i i"l J"l J- 1 u Ui mi i ii AJ002962  35185 at -I * 1 * Ί Ί • i i "l J" l J- 1 u Ui mi i ii AJ002962
36979 at u 11 u u u u u u ΪΪ i 11 u ί Μ20681  36979 at u 11 u u u u u u ΪΪ i 11 u ί 68120681
37582 at Ϊ i I 11 u u 1 u i il ill Χ07696  37582 at Ϊ i I 11 u u 1 u i il ill Χ07696
38772 at ii Ί Ί Ί ii l 11 ill Ul Ul 1 1 I Υ11307  38772 at ii Ί Ί ii ii l 11 ill Ul Ul 1 1 I Υ11307
39822 s at ii a u ΪΪ u u 11 •i i"i u 1 1 u m m AF078077  39822 s at ii a u ΪΪ u u 11 • i i "i u 1 1 u m m AF078077
595一 at u 11 11 11 u 11 11 il 11 11 11 u † † †† 59465  595 at u 11 11 11 u 11 11 il 11 11 11 u † † †† 59465
¾〇〇1 表 1 0 1 ¾〇〇1 Table 10 1
ァトピー性皮膚炎患者の無疹部と健常人の正常組織間の比較で、 ァトピー性皮 膚炎患者の無疹部で発現が減少していた遺伝子 （表 1 3〜表 1 5および表 2 2〜 表 2 4 ) とサイトカイン刺激ケラチノサイトと無刺激ケラチノサイト間で発現が 変動した遺伝子 （表 9 9〜表 1 0 0 ) の説明を示した。 In comparison between the eruptions of atopic dermatitis patients and the normal tissues of healthy subjects, genes whose expression was decreased in the eruptions of atopic dermatitis patients (Tables 13 to 15 and Table 22) Table 24) and explanations of genes (Tables 99 to 100) whose expression fluctuated between cytokine-stimulated keratinocytes and unstimulated keratinocytes.
Figure imgf000343_0001
Figure imgf000343_0001
CO CO
CO  CO
Figure imgf000344_0001
Figure imgf000344_0001
5 一 at M5946 tumor necross actor ap a in uc e proten 2  5 Ichi at M5946 tumor necross actor ap a in uc e proten 2
¾〇1 産業上の利用の可能性 ¾〇1 Industrial potential
本発明は、 以下の a) -d)、 c，）および d' )、 並びに A) - D)の各群に示すアトピー性 皮膚炎の指標遺伝子を提供する。  The present invention provides indicator genes for atopic dermatitis shown in the following groups a) -d), c,) and d '), and A) -D).
a) 皮疹部における発現レベルがアトピー性皮膚炎患者の無疹部に比べて高い指 標遺伝子群：  a) Marker genes whose expression level in the rash area is higher than that in the non-rash area of atopic dermatitis patients:
b) 皮疹部における発現レベルがアトピー性皮膚炎患者の無疹部に比べて低い指 標遺伝子群：  b) Marker genes whose expression level in the rash area is lower than that in the non-rash area in patients with atopic dermatitis:
c) および c' )アトピー性皮膚炎患者の無疹部における発現レベルが健常者の発 現レベルに比べて高い指標遺伝子群：  c) and c ') Indicator gene groups whose expression levels in the eruption area of patients with atopic dermatitis are higher than those in healthy subjects:
d) および d' )ァトピー性皮膚炎患者の無疹部における発現レベルが健常者の発 現レベルに比べて低い指標遺伝子群：  d) and d ') Indicator gene groups whose expression levels in the eruption area of patients with atopic dermatitis are lower than those in healthy subjects:
A)以下の遺伝子からなる、 ダニァレルゲン感作マゥスの耳介皮膚における発現 レベルがダユアレルゲン非感作マゥスの耳介皮膚に比べて高い指標遺伝子群： A) An indicator gene group consisting of the following genes, the expression level of which is higher in the auricle skin of mite-sensitized mice compared to the auricle skin of day-allergen-unsensitized mice:
B)以下の遺伝子からなる、 ダニァレルゲン感作マウスの耳介皮膚における発現 レベルがダニアレルゲン非感作マウスの耳介皮膚に比べて低い指標遺伝子群：B) An indicator gene group comprising the following genes, whose expression level in the auricle skin of mite allergen-sensitized mice is lower than that of the mite allergen non-sensitized mice:
C) DNFB反復塗布接触性皮膚炎モデルマゥスの耳介皮膚における発現レベルが D F B反復塗布前のマウスの耳介皮膚に比べて高い指標遺伝子群： C) Marker gene group whose expression level in the auricle skin of DNFB repeated application contact dermatitis model mouse is higher than that of the mouse auricle skin before repeated application of DFB:
D) DNFB反復塗布接触性皮膚炎モデルマウスの耳介皮膚における発現レベルが DNF B反復塗布前のマウスの耳介皮膚に比べて低い指標遺伝子群：  D) Expression genes whose expression levels in the auricle skin of DNFB repeated application contact dermatitis model mice are lower than in the auricle skin of mice before repeated application of DNFB:
各遺伝子の発現レベルを指標とすることにより、 アトピー性皮膚炎の検査方法、 ァレルギ一性疾患モデル動物の作成、 およぴ該疾患の治療のための化合物をスク リーユングすることが可能となった。  By using the expression level of each gene as an index, it became possible to test atopic dermatitis, create animal models of allergic diseases, and screen compounds for the treatment of the diseases. .
加えて本発明は、 以下の i)〜iv)の各群に示す乾癬の指標遺伝子を提供する。 i)乾癬の患者において皮疹部における発現レベルが無疹部に比べて高い指標遺 伝子群：  In addition, the present invention provides indicator genes for psoriasis shown in the following groups i) to iv). i) Marker gene group whose expression level in the rash area is higher than that in the non-rash area in patients with psoriasis:
ϋ) 乾癬の患者において皮疹部における発現レベルが無疹部に比べて低い指標 遺伝子群： 指標) Indices in which the expression level in the rash area is lower in psoriatic patients than in the rash area Gene group:
i i i) 乾癬患者の無疹部における発現レベルが健常者の発現レベルに比べて高レ、 指標遺伝子群：  i i i) The expression level in the rash area of psoriasis patients is higher than that in healthy subjects.
iv) 乾癬患者の無疹部における発現レベルが健常者の発現レベルに比べて低 ヽ 指標遺伝子群：  iv) The expression level in the rash area of psoriatic patients is lower than that in healthy subjects.
本発明の各指標遺伝子は、 その発現の変化が病態と結びついている。 したがつ て指標遺伝子の発現や、 指標遺伝子によってコードされる蛋白質 活性を調節す ることによってアトピー性皮膚炎または乾癬の治療が可能となる。 例えば患部や 患者の皮膚において発現が上昇する遺伝子の場合には、 発現やその活性を阻害す ることが、 アトピー性皮膚炎または乾癬の治療戦略のターゲットとなる。 逆に発 現が低下する遺伝子の場合には、 発現や活性を促進することが、 アトピー性皮膚 炎または乾癬の治療戦略のターゲットとなる。 また、 これらの指標遺伝子は、 ァ トビー性皮膚炎または乾癬の治療におけるモニタリングのための新しい臨床診断 指標としての有用性が期待できる。  For each indicator gene of the present invention, a change in its expression is linked to a disease state. Therefore, by modulating the expression of the indicator gene and the activity of the protein encoded by the indicator gene, it becomes possible to treat atopic dermatitis or psoriasis. For example, in the case of a gene whose expression is increased in the affected area or in the skin of a patient, inhibition of the expression or its activity is a target of a treatment strategy for atopic dermatitis or psoriasis. Conversely, in the case of genes whose expression is reduced, enhancing their expression and activity is the target of therapeutic strategies for atopic dermatitis or psoriasis. In addition, these indicator genes are expected to be useful as new clinical diagnostic indicators for monitoring in the treatment of arthritis dermatitis or psoriasis.
本発明によって提供された各指標遺伝子は、 アレルゲンの種類に関わらず、 簡 便にその発現レベルを知ることができる。 従って、 アレルギー反応の病態を総合 的に把握することができる。  The expression level of each indicator gene provided by the present invention can be easily known regardless of the type of allergen. Therefore, the pathology of allergic reactions can be comprehensively understood.
また本発明によるァトピー性皮膚炎の検査方法は、 生体試料を試料としてその 発現レベルを解析することができるので、 患者に対する侵襲性が低い。 しかも遺 伝子発現解析に関しては、 微量サンプルによる高感度な測定が可能である。 遺伝 子解析技術は、 年々ハイスループット化、 低価格ィ匕が進行している。 従って本発 明によるアトピー性皮膚炎の検査方法は、 近い将来、 医療現場における重要な診 断方法となることが期待される。 この意味で本発明の指標遺伝子の診断的価値は 高い。  In addition, the method for testing atopic dermatitis according to the present invention can analyze the expression level of a biological sample as a sample, and therefore has low invasiveness to patients. In addition, with regard to gene expression analysis, highly sensitive measurement using a small amount of sample is possible. In gene analysis technology, high throughput and low price are increasing year by year. Therefore, the method of testing for atopic dermatitis according to the present invention is expected to be an important diagnostic method in medical practice in the near future. In this sense, the diagnostic value of the indicator gene of the present invention is high.

Claims

請求の範囲  The scope of the claims
1 . 次の工程 ( 1 ) 〜 （3 ) を含む、 アトピー性皮膚炎の検査方法であって、 指標遺伝子が次の a)〜d)、 並びに c' )および d，）のいずれかに記載の群から選 択されたいずれかの遺伝子である方法。 1. A method for testing atopic dermatitis, comprising the following steps (1) to (3), wherein the indicator gene is described in any of the following a) to d), and c ') and d,) The method is any gene selected from the group of.
( 1 ) 被検者の皮疹部おょぴ Zまたは無疹部から採取された生体試料における 指標遺伝子の発現レベルを測定する工程  (1) A step of measuring the expression level of an indicator gene in a biological sample collected from the skin eruption area Z or the eruption area of the subject
( 2 ) 工程 ( 1 ) で測定された発現レベルを、 指標遺伝子が a)または b)に記 載された遺伝子である場合には、 対照として同じ被検者の無疹部から採取 された生体試料における指標遺伝子の発現レベルと、 また指標遺伝子が c；)、 c' )、 d)、 および d' )のいずれかに記載された遺伝子である場合には、 対照 として健常者の生体試料における指標遺伝子の発現レベルと比較する工程、 および  (2) When the expression level measured in step (1) is the gene described in a) or b), the expression level measured in step (1) is the same as the control. The expression level of the indicator gene in the sample, and if the indicator gene is a gene described in any of c;), c '), d), and d'), the control gene Comparing with the expression level of the indicator gene; and
( 3 ) 工程 ( 2 ) の比較の結果、 指標遺伝子が a)、 c)および c )に記載された 遺伝子の場合には対照と比較して発現レベルが高い場合に、 また指標遺伝 子が b)、 d)および d' )に記載された遺伝子の ^^には対照と比較して発現 レベルが低い場合に、 前記被検者はァトピー性皮膚炎を有すると判定する 工程  (3) As a result of the comparison in step (2), when the indicator gene is a gene described in a), c) and c), the expression level is higher than the control, and the indicator gene is b A) determining that the subject has atopic dermatitis when the expression level of ^^ of the gene described in d) and d ′) is lower than that of the control.
a) 以下の遺伝子からなる、 ^疹部における発現レベルがアトピー' 14皮膚炎患 者の無疹部に比べて高い指標遺伝子群： cathepsin C、 metalloproteinase (HM a) A group of indicator genes consisting of the following genes, whose expression level in the rash area is higher than that in the non-rash area in atopic dermatitis patients: cathepsin C, metalloproteinase (HM
、 airway trypsin一 liKe protease^ type IV collagenase cathepsin Z prec ursor (CTS¾、 disintegrin-proteaseN serine protease-like proteinN pro— c athepsin L (major excreted protein MEP)、 protease M、 skin collagenase、 trypsinogen IV b-form SPUVE (protease, serine, 23)、 Proprotein convert ase subtilisin/kexin typel、 neutrophil gelatinase associated lipoca丄 inヽ squamous cell carcinoma antigen=serine protease inhibitor s squamous eel 1 carcinoma antigen 2 (SCCA2)、 tissue inhibitor of metalloproteinasesN mononcyte/ne trophi 1 elastase inhibitor^ alpha 1 - antitrypsin beta-migr ating plasminogen activator inhibitor I、 elafin、 interleukin-7 receptor、 IL-13R al、 IFN - beta 2a (interleukin 6)、 interleukin 4 receptor % platele t - derived endothelial cell growth factor、 pre - B cell enhancing factor (PBEF)、 heparin- binding EGF-like growth factor, GM-CSFR beta, interleuk in 8 (IL8)、 alternative activated macrophage specific CC c emokine 1、 M CP - 1、 EBIl-ligand chemokine、 SIX、 lactotransferrin GRO - beta、 monocyte chemotactic protein - 2ゝ CCR1、 mel noma growth stimulatory activity (MGS A) I Gro alpha, psoriasin (S100A7〉、 MRP - 8 (S100A8)、 MRP—14(S100A9)、 CaN 19 (S100A2)、 p cadherin lymph node homing receptor / L - selectin、 endoth e丄 lal leukocyte adhesion molecule 1 (ELAM - 1)、 130-kD pemphigus vulgaris antigen / Desmoglein 3、 leukocyte adhesion protein (LFA - 1/Mac- l/pl50， 9 5 family) beta、 desmocollins type 2b、 TNFAIP6 (tumor necrosis factor, a 丄 pha— induced protein 6)、 CD24 signal transducer Λ Ml 30 antigen extracell ular variant / CD163ヽ 0A3 antigenic surface determinant / CD47、 CD53 gl ycoproteinゝ T200 leukocyte common antigen (CD45) isoformU T200 leukocy te common antigen (CD45) isoform2^ T200 leukocyte common antigen (CD45) isoform3、 ΓΗΥ-l (CD90)、 monocyte/macrophage Ig-related receptor MIR— 7 I CD85、 leucocyte immunoglobulin - like receptor - 3 (LIR - 3)、 " enascin - C、 a lpha-1 type XV collagen^ cartilage oligomeric matrix protein (C0MP)、 pr oteogl can 1、 immunoglobulin lambda light chain Fc - epsilon— receptor ga mma-chain IgG low affinity Fc fragment receptor (CD32)、 immunoglobulin heavy constant gamma 3 (G3m marker imnrnnoglobulin kappa constant^ ly n、 hemopoietic cell protein - tyrosine kinase (HCK)、 protein tyrosine pho sphatase, receptor type, E isoforml、 protein tyrosine phosphatase, rece O 2004/031386 , Airway trypsin-one liKe protease ^ type IV collagenase cathepsin Z prec ursor (CTS¾, disintegrin-protease N serine protease-like protein N pro- c athepsin L (major excreted protein MEP), protease M, skin collagenase, trypsinogen IV b-form SPUVE (protease, serine, 23), Proprotein convertase subtilisin / kexin typel, neutrophil gelatinase associated lipoca 丄 in ヽ squamous cell carcinoma antigen = serine protease inhibitor s squamous eel 1 carcinoma antigen 2 (SCCA2), tissue inhibitor of metalloproteinases N mononcyte / netrophi 1 elastase inhibitor ^ alpha 1-antitrypsin beta-migr ating plasminogen activator inhibitor I, elafin, interleukin-7 receptor, IL-13R al, IFN-beta 2a (interleukin 6), interleukin 4 receptor % platelet-derived endothelial cell growth factor, pre-B cell enhancing factor (PBEF), heparin-binding EGF-like growth factor, GM-CSFR beta, interleuk in 8 (IL8), alternative activated macrophage specific CC c emokine 1, M CP-1, EBIl-ligand chemokine, SIX, lactotransferrin GRO-beta, monocyte chemotactic protein-2 ゝ CCR1, mel noma growth stimulatory activity (MGS A) I Gro alpha, psoriasin (S100A7) , MRP-8 (S100A8), MRP-14 (S100A9), CaN 19 (S100A2), p cadherin lymph node homing receptor / L-selectin, endoth e 丄 lal leukocyte adhesion molecule 1 (ELAM-1), 130-kD pemphigus vulgaris antigen / Desmoglein 3, leukocyte adhesion protein (LFA-1 / Mac- l / pl50, 95 family) beta, desmocollins type 2b, TNFAIP6 (tumor necrosis factor, a 丄 pha— induced protein 6), CD24 signal transducer Λ Ml 30 antigen extracellular variant / CD163 ヽ 0A3 antigenic surface determinant / CD47, CD53 gl ycoprotein ゝ T200 leukocyte common antigen (CD45) isoformU T200 leukocyte common antigen (CD45) isoform2 ^ T200 leukocyte common antigen (CD45) isoform3, ΓΗΥ-l (CD90), monocyte / macrophage Ig-related receptor MIR— 7 I CD85, leucocyte immunoglobulin-like receptor-3 (LIR-3), "enascin-C, a lpha-1 type XV collagen ^ cartilage oligomeric matrix protein (C0MP), pr oteogl can 1, immunoglobulin lambda light chain Fc-epsilon— receptor ga mma -chain IgG low affinity Fc fragment receptor (CD32), immunoglobulin heavy constant gamma 3 (G3m marker imnrnnoglobulin kappa constant ^ ly n, hemopoietic cell protein-tyrosine kinase (HCK), protein tyrosine pho sphatase, receptor type, E isoforml, protein tyrosine phosphatase, rece O 2004/031386
3 4 8； 3 4 8;
ptor type, E isoform2、 KIAA0687 / MAP4K4、 tartrate-resistant acid phosp hatase type 5、 cholesterol 25-hydroxylase^ Phospholipid scramblase 1、 m anganese superoxide dismutase (EC 1. 15. 1. 1)、 ornithine decarboxylase 0D C (EC 4. 1· 1. 17)、 phospholipase A2, group IIA (platelets, synovial flui d)、 nicotinamide N-methyltransf erase (NNMT)、 uridine phosphorylase^ aid ose reductase - like peptide^ 2'， 5， oligoadenylate synthetase isoform E16、 2'， 5' oligoadenylate synthetase isoform E18、 2，， 5， oligoadenylate synth etase 2 isoform p69、 2，， 5， oligoadenylate synthetase 2 isoform p71、 L-k ynurenine hydrolase^ purine nucleoside phosphorylase (PNP ; EC 2· 4. 2. 1)、 2，，5， oligoadenylate synthetase-丄 ike (59 kDa isoform)、 cytokeratin 17、 keratin 6A、 keratin 16、 actin related protein 2/3 complex, sub unit IB (41 kD)、 myosin VA (heavy polypeptide 12, myo in) Small proline- rich p rotein SPRK、 small proline— rich protein 2A、 small proline- rich protein IB (cornifin)、 involucrin myosin IB、 interferon-inducible protein p78 (MX1)、 gamma- interferon - inducible protein (IP - 30〉、 interferon - induced 1 ト kDa/15 - kDa protein^ p27， interferon-alpha-inducible protein 27、 RAB31、 regulator of G - protein signalling 1 (BL34) regulator of G- protein sign ailing 20、 STAT1、 TNRC3、 insulin-like growth factor binding protein 4 (IGFBP4)、 cyclin B、 proto -oncogene (Wnt -!) aノ、 beta defensin 2 (HBD2)、 ne 丄-; related protein 2、 neuronal tissue-enriched acidic protein (NAP - 22)、 DE Zp58600118 / KI 1199、 lysosomal - associated multi transmembrane prote in (LAPTm5)、 KIM0101、 KI 0296、 serum amyloid Al、 tumor suppressing su b transferable candidate 3 (TSSC3)、 TYRO protein tyrosine kinase binding protein^ fatty acid binding protein homologue (PA-FABP)、 heparin bindi ng protein (HBpl7) I FGF - BP1、 trans cobal ami n Iヽ fibrinogen- like 2ヽ ぉょ び six transmembrane epithelial antigen of the prostate (STEAP) b) 以下の遺伝子からなる、 皮疹部における発現レベルがアトピー性皮膚炎患 者の無瘆部に比べて低い指標遺伝子群： kallikrein 1、 cathepsin V、 cystatin n/M、 SERPI B7 ^serine (or cysteine; proteinase inhibitor, clade B (ova lbumin) , member 7)、 tissue inhibitor of metalloproteinase 4、 KIAA1775 (MT-protocadherin) keratin 18、 cytokeratin 15、 keratin 19、 smooth muse le myosin heavy chain 11， isoform SM2、 sciellin (SCEL>)、 KIAA0353/desmus 丄 in (intermediate filament protein) calponin 1、 desmin、 extracellular matrix protein 2、 protein— tyrosine— phosphatase Dl、 KIAA0537、 angiogenin (RNase A family, 5)、 RNase 4ゝ deoxyribonuclease I - like 2 (DNAS1L2) s p hosphoenolpyruvate carboxykinase (PCK1)、 carbonic anhydrase isozyme VI (CA6) N 3- hydroxy - 3 - methylglutaryl coenzyme A synthase^ arylacetamide de acety丄 ase、 ATPase, Cu++ transporting, alpha polypeptide (ATP7A)、 tyrosi nase (TYR) ^ amylase, alpha 2B; pancreatic^ CMP-N-acetylneuraminic acid hydroxylase^ Aminomethyltransf erase (glycine cleavage system protein T)、 monoamine oxidase A、 Aldehyde dehydrogenase 5 family, member Al、 CYTOCH ROME P450, SUBFAMILY IIIA， POLYPEPTIDE 5、 alcohol dehydrogenase 1A (cla ss I) , alpha polypeptide、 alcohol dehydrogenase IB (class I), beta poly peptide^ alcohol dehydrogenase 1C (class I) , gamma polypeptide^ degener a ive spermatocyte homo log (sphingolipid delta 4 desaturase) ^ FABP7 (fa tty acid binding protein 7)、 alpha - 2 - glycoprotein 1， zinc、 perilipin、 F ABP4 (Fatty acid binding protein 4)、 lipoprotein lipase^ aldehyde dehyd rogenase 3 family, member A2、 phytanoyl-CoA hydroxylase interacting pro tein (KIAA027'3)、 apolipoprotein D、 apolipoprotein E、 Hemoglobin alpha 1 chain (HBA1)、 Hemoglobin alpha 2 chain (HBA2)、 hemoglobin, gamma A (HB Gl)、 hemoglobin, gamma G (HBG2)、 hemoglobin, beta、 mammaglobin 1、 mamma gloDin 2、 secretoglobin, fami ly ID, member 2、 delta sleep inducing pept ide, immunoreactor^ class I homeoprotein (H0XA9)、 beta-catenin-interact ing protein ICAT、 promyelocytic leukemia zinc finger protein (PLZF)、 GA TA3、 forkhead/winged helix-like transcription factor 7 (FKHL7) s Inhibit or of DNA binding 4 (ID4)、 calcium channel, voltage-dependent, alpha 1H subunit、 sodium channel, nonvoltage-gated 1， beta、 Beta-microseminopro tein isoform a (PSP94)、 Beta-mi croseminoprote in isoform b (PSP57)、 test icular inhibin beta-B- subunit、 LIGl (ortholog of mouse integral membran e glycoprotein LIG-1)、.WFS1 (Wolfram syndrome 1)、 TM4SF3 (transmembraneptor type, E isoform2, KIAA0687 / MAP4K4, tartrate-resistant acid phosp hatase type 5, cholesterol 25-hydroxylase ^ Phospholipid scramblase 1, manganese superoxide dismutase (EC 1.15.1.1), ornithine decarboxylase 0D C (EC 4 1.1.17), phospholipase A2, group IIA (platelets, synovial fluid), nicotinamide N-methyltransf erase (NNMT), uridine phosphorylase ^ aid ose reductase-like peptide ^ 2 ', 5, oligoadenylate synthetase isoform E16, 2 ', 5' oligoadenylate synthetase isoform E18, 2 ,, 5, oligoadenylate synth etase 2 isoform p69, 2 ,, 5, oligoadenylate synthetase 2 isoform p71, Lk ynurenine hydrolase ^ purine nucleoside phosphorylase (PNP; EC 2.4.2. 1), 2, 5, oligoadenylate synthetase- 丄 ike (59 kDa isoform), cytokeratin 17, keratin 6A, keratin 16, actin related protein 2/3 complex, sub unit IB (41 kD), myosin VA (heavy polypeptide 12) , myo in) Small proline- rich protein SPRK, small proline— rich protein 2A, small proline-rich protein IB (cornifin), involucrin myosin IB, interferon-inducible protein p78 (MX1), gamma-interferon-inducible protein (IP-30), interferon-induced 1 kDa / 15-kDa protein ^ p27, interferon- alpha-inducible protein 27, RAB31, regulator of G-protein signaling 1 (BL34) regulator of G- protein sign ailing 20, STAT1, TNRC3, insulin-like growth factor binding protein 4 (IGFBP4), cyclin B, proto-oncogene ( Wnt-!) A, beta defensin 2 (HBD2), ne 丄-; related protein 2, neuronal tissue-enriched acidic protein (NAP-22), DE Zp58600118 / KI 1199, lysosomal-associated multi transmembrane prote in (LAPTm5) , KIM0101, KI0296, serum amyloid Al, tumor suppressing sub transferable candidate 3 (TSSC3), TYRO protein tyrosine kinase binding protein ^ fatty acid binding protein homologue (PA-FABP), heparin bindin ng protein (HBpl7) I FGF-BP1 , Trans cobal ami n I ヽ fibrinogen- like 2 ヽ ぉ び trans six transmembrane epithelia l antigen of the prostate (STEAP) b) Indicator genes consisting of the following genes, whose expression level in the rash area is lower than that in the atopic area of atopic dermatitis patients: kallikrein 1, cathepsin V, cystatin n / M, SERPI B7 ^ serine (or cysteine) ; proteinase inhibitor, clade B (ova lbumin), member 7), tissue inhibitor of metalloproteinase 4, KIAA1775 (MT-protocadherin) keratin 18, cytokeratin 15, keratin 19, smooth muse le myosin heavy chain 11, isoform SM2, sciellin (SCEL >), KIAA0353 / desmus 丄 in (intermediate filament protein) calponin 1, desmin, extracellular matrix protein 2, protein- tyrosine- phosphatase Dl, KIAA0537, angiogenin (RNase A family, 5), RNase 4 ゝ deoxyribonuclease I-like 2 ( DNAS1L2) s p hosphoenolpyruvate carboxykinase (PCK1 ), carbonic anhydrase isozyme VI (CA6) N 3- hydroxy - 3 - methylglutaryl coenzyme A synthase ^ arylacetamide de acety丄ase, ATPase, Cu ++ transporting, alpha polypeptide (ATP7A), tyrosi nase (TYR ) ^ amylase, alpha 2 B; pancreatic ^ CMP-N-acetylneuraminic acid hydroxylase ^ Aminomethyltransf erase (glycine cleavage system protein T), monoamine oxidase A, Aldehyde dehydrogenase 5 family, member Al, CYTOCH ROME P450, SUBFAMILY IIIA, POLYPEPTIDE 5, alcohol dehydrogenase 1A (cla sss I), alpha polypeptide, alcohol dehydrogenase IB (class I), beta poly peptide ^ alcohol dehydrogenase 1C (class I), gamma polypeptide ^ degener a ive spermatocyte homo log (sphingolipid delta 4 desaturase) ^ FABP7 (fa tty acid binding protein 7) ), Alpha-2-glycoprotein 1, zinc, perilipin, FABP4 (Fatty acid binding protein 4), lipoprotein lipase ^ aldehyde dehyd rogenase 3 family, member A2, phytanoyl-CoA hydroxylase interacting pro tein (KIAA027'3), apolipoprotein D , Apolipoprotein E, Hemoglobin alpha 1 chain (HBA1), Hemoglobin alpha 2 chain (HBA2), hemoglobin, gamma A (HB Gl), hemoglobin, gamma G (HBG2), hemoglobin, beta, mammaglobin 1, mamma gloDin 2, secretoglobin, fami ly ID, me mber 2, delta sleep inducing pept ide, immunoreactor ^ class I homeoprotein (H0XA9), beta-catenin-interacting protein ICAT, promyelocytic leukemia zinc finger protein (PLZF), GA TA3, forkhead / winged helix-like transcription factor 7 (FKHL7) s Inhibit or of DNA binding 4 (ID4), calcium channel, voltage-dependent, alpha 1H subunit, sodium channel, nonvoltage-gated 1, beta, Beta-microseminoprotein isoform a (PSP94), Beta-microseminoprote in isoform b (PSP57), test icular inhibin beta-B-subunit, LIGl (ortholog of mouse integral membran e glycoprotein LIG-1), .WFS1 (Wolfram syndrome 1), TM4SF3 (transmembrane
4 superfamily member 3)、 ITM2A (integral memkrane protein 2A)、 claudin4 superfamily member 3), ITM2A (integral memkrane protein 2A), claudin
8、 syndecan 4 (amphiglycan, ryudocan)ヽ progesterone receptor membrane component 2、 peanut-like 1 (Drosophilaノ、 type 1 angiotensin II receptor, variant 1-5、 EphB6、 proteolipid proteinic betacellulin^ apMl (adipose most abundant gene transcript 1)、 roline rich 4 (lacrimal)、 rolactin- inducible prot;ein、 HZF9、 skin-specific protein (xp32)、 Crystal 1 in, alph a B、 retinol binding protein 4、 Hepatocellular carcinoma antigen gene 5 20、 DKFZP434G0310 (hypothetical protein)、 Purkinje cell protein 4 (PCP 4)、 141H5、 cyclin Dl、 loricrin^ TRIM2 (tripartite motif-containing 2)、 metallothionein IV (MTIV)、 DKFZp586H2123、 transmembrane 4 superfamily m ember 11 (plasmolipin)、 D FZp434A202 KIM0471、 ΠΜ0450、 KIAA0624, KIA A0633, partial cds、 KIAA0456, partial cds、 DKFZp564D206 DKFZp586F1223、 Clorf21、 および DKFZp761F2014 8, syndecan 4 (amphiglycan, ryudocan) ヽ progesterone receptor membrane component 2, peanut-like 1 (Drosophila, type 1 angiotensin II receptor, variant 1-5, EphB6, proteolipid proteinic betacellulin ^ apMl (adipose most abundant gene transcript 1) , Roline rich 4 (lacrimal), rolactin-inducible prot; ein, HZF9, skin-specific protein (xp32), Crystal 1 in, alph a B, retinol binding protein 4, Hepatocellular carcinoma antigen gene 520, DKFZP434G0310 (hypothetical protein) , Purkinje cell protein 4 (PCP 4), 141H5, cyclin Dl, loricrin ^ TRIM2 (tripartite motif-containing 2), metallothionein IV (MTIV), DKFZp586H2123, transmembrane 4 superfamily member 11 (plasmolipin), D FZp434A202 KIM0471, ΠΜ0 KIAA0624, KIA A0633, partial cds, KIAA0456, partial cds, DKFZp564D206 DKFZp586F1223, Clorf21, and DKFZp761F2014
c) 以下の遺伝子からなる、 アトピー性皮膚炎患者の無疹部における発現レべ ルが健常者の発現レベルに比べて高い指標遺伝子群： P13- kinase associated p 85、 pnosphoenolpyruvate carboxykinase (PCK1)、 nucleotide pyrophosphatas e、 L-3-phosphoserine phosphatase^ L一 3— phosphoserine- phosphatase homo log ue、 KIAA0369/doublecortin and CaM kinase - like 1、 tartrate— resistant aci 3 5 1: — ― i , c) Indicator genes consisting of the following genes, whose expression level in the eruption area of atopic dermatitis patients is higher than that in healthy subjects: P13-kinase associated p85, pnosphoenolpyruvate carboxykinase (PCK1), nucleotide pyrophosphatas e, L-3-phosphoserine phosphatase ^ L-1- 3-phosphoserine- phosphatase homo log ue, KIAA0369 / doublecortin and CaM kinase-like 1, tartrate- resistant aci 3 5 1: — ― i,
d phosphatase type 5、 pM5 protein^ ADA 9 (a disintegrin and metalloprot einase domain 9)、 Ubiquitin - conjugating enzyme E2E 1、 DKFZp586H2123 SP UVE (protease, serine, 23)、 squamous cell carcinoma antigen 2 (SCCA2) N connexin 43 (GJAl, Cx43)、 plakophilin^ desmocollin type 4、 integrin alp ha - 2 subunit、 H-cadherin^ neural cell adhesion molecule (CALL) N cart i la ge intermediate layer protein (CI LP) lumican、 chondroitin sulphate pro teoglycan vers i can, VI spl ice - variant、 germl ine oligoraeric matrix prote in (C0MP)、 aspartylglucosaminidase、 lysyl hydroxylase isoform 2 (PL0D2) phospholipase A2, group IIA (platelets, synovial fluid)、 GDP-L- fucose p yr ophosphory 1 as e (GFPP)、 glycogen debranching enzyme isoform 1 (AGL) ， alternatively spliced isoform、 Gu protein/DDX21: DEAD/H (Asp - Glu- Ala-As p/His) box polypeptide 21、 lipoprotein lipase^ SMA5、 hemoglobin, alpha 1、 hemoglobin, alpha 2、 sickle cell beta-globinN beta-globin (HBB)、 A— g amma globin、 G-gamma globin、 phospholipid transfer prote in% ATP-binding cassette, sub-family G (WHITE) , member 1、 type 2 inositol 1, 4, 5-trisph osphate receptor MVP (major vault protein)、 C0G5 (component of oligome ric golgi complex 5)、 S100 calcium-binding protein A7 (psoriasin 1)、 Ca N19、 immunoglobulin lambda light chain、 immunoglobulin heavy constant g amma 3、 immunoglobulin kappa constant^ major histocompatibility complex, class II， DQ beta 1、 CIQB (complement component 1, q subcomponent, bet a polypeptide)、 Guanine Nucleotide-Binding Protein Ral, Ras— Oncogene Re lated^ ΚΓ 0440, 議 5、 KIAA0400/devel opment- and dif f erentiat ion-enhanc ing factor 2、 alternative activated macrophage specific CC chemokine 1、 CC-chemokine MCP - 4、 small proline - rich protein IB (cornif in) myosin he avy chain 12 (MY05A)、 M0P3、 RB18A、 TTF- I interacting peptide 12/RNA pold phosphatase type 5, pM5 protein ^ ADA 9 (a disintegrin and metalloprot einase domain 9), Ubiquitin-conjugating enzyme E2E 1, DKFZp586H2123 SP UVE (protease, serine, 23), squamous cell carcinoma antigen 2 (SCCA2) N connexin 43 ( GJAl, Cx43), plakophilin ^ desmocollin type 4, integrin alp ha-2 subunit, H-cadherin ^ neural cell adhesion molecule (CALL) N cart i lage intermediate layer protein (CI LP) lumican, chondroitin sulphate pro teoglycan vers i can , VI spl ice-variant, germl ine oligoraeric matrix prote in (C0MP), aspartylglucosaminidase, lysyl hydroxylase isoform 2 (PL0D2) phospholipase A2, group IIA (platelets, synovial fluid), GDP-L- fucose p yr ophosphory 1 as e ( GFPP), glycogen debranching enzyme isoform 1 (AGL), alternatively spliced isoform, Gu protein / DDX21: DEAD / H (Asp-Glu-Ala-As p / His) box polypeptide 21, lipoprotein lipase ^ SMA5, hemoglobin, alpha 1, hemoglobin, alpha 2, sickle cell beta-globin N beta-globin (HBB), A— g a mma globin, G-gamma globin, phospholipid transfer prote in % ATP-binding cassette, sub-family G (WHITE), member 1, type 2 inositol 1, 4, 5-trisph osphate receptor MVP (major vault protein), C0G5 ( component of oligome ric golgi complex 5), S100 calcium-binding protein A7 (psoriasin 1), Ca N19, immunoglobulin lambda light chain, immunoglobulin heavy constant gamma 3, immunoglobulin kappa constant ^ major histocompatibility complex, class II, DQ beta 1, CIQB (complement component 1, q subcomponent, bet a polypeptide), Guanine Nucleotide-Binding Protein Ral, Ras— Oncogene Related ^ ΚΓ 0440, r 5, KIAA0400 / development- and dif erentiat ion-enhancing factor 2, alternative activated macrophage specific CC chemokine 1, CC-chemokine MCP-4, small proline-rich protein IB (cornif in) myosin he avy chain 12 (MY05A), M0P3, RB18A, TTF-I interacting peptide 12 / RNA pol
I and transcript release factor^ Mad4 homo log (Mad4)、 pituitary tumor- O 2004/031386 I and transcript release factor ^ Mad4 homo log (Mad4), pituitary tumor- O 2004/031386
3 5 2； 3 5 2;
transforming protein 1、 SMAD5、 G0S2、 cyclin B、 Retinoblastoma 1、 M130 a ntigen extracellular variant (CD163)、 Z39IG、 perilipin、 apMl (adipose m ost abundant gene transcript 1)、 DKFZp586J0323 KIAA1001 KIAA0766N KIA A0101、 DJ971N18. 2/KIM1162、 lung type- 1 cell membrane - associated protei n (Tla - 2)、 metal lothionein IV (MTIV)、 UTY (ubiquitously transcribed tet ratricopeptide repeat gene, Y chromosome) Λ Apg - 1、 HUNKI/MCAP^ FHL2 (fou r and a half LIM domains 2)、 RBP4 (retinol binding protein 4, plasma)、 および ALG- 2/programmed cell death 6 transforming protein 1, SMAD5, G0S2, cyclin B, Retinoblastoma 1, M130 antigenic extracellular variant (CD163), Z39IG, perilipin, apMl (adipose most abundant gene transcript 1), DKFZp586J0323 KIAA1001 KIAA0766 N KIAA1161 , Lung type-1 cell membrane-associated protein (Tla-2), metal lothionein IV (MTIV), UTY (ubiquitously transcribed tet ratricopeptide repeat gene, Y chromosome) Λ Apg-1, HUNKI / MCAP ^ FHL2 (fou r and a half LIM domains 2), RBP4 (retinol binding protein 4, plasma), and ALG-2 / programmed cell death 6
c' ) 以下の遺伝子からなる、 アトピー性皮膚炎患者の無疹部における発現レ ベルが健常者の発現レベルに比べて高い指標遺伝子群： transforming growth f actor, beta receptor III (betaglycan, 300kD)、 BTF3 protein homologueヽ h emogloDin, alpha 1、 hemoglobin, beta、 alternative activated macrophage specific CC chemokine 1、 Pro lact in-Induced ProteinN branched chain alph a-ketoacid dehydrogenase kinase^ type I sigma receptor isoform 1、 type I sigma receptor isoform 2、 type I sigma receptor isoform 3、 type I sig ma receptor isoform 4、 type I sigma receptor isoform 5、 KIAA0664 protei n、 FK506 - binding protein IB isoform a、 FK506-binding protein IB isoform b、 lymphoid -: restricted membrane protein (L MP)、 specific granule prote in (28 kDa) (SGP28)、 ATPase, Ca++ transporting, ubiquitous^ general tra ascription factor I IF, polypeptide 2, 30kDa、 carboxypeptidase M、 tyrosi nase - related protein 1、 HCR (a - helix coiled-coil rod homologue)、 FLJ125 25、 A— gamma glo in^ complement component 1, q subcomponent, beta polype ptide、 SET binding factor 1 (SBF1)、 hi stidine ammonia - lyase、 KIM0440、 ES i s, Moderately simi lar to 2004399A chromosomal protein^ gap junction protein, beta 3, 31kD (connexin 31)、 androgen- regulated short-chain deh ydrogenase/reductase 1、 nuclear receptor subfamily 1， group H, member 2、 matrilysin (MMP7)、 およぴ runt- related transcription factor 1 c ') An indicator gene group consisting of the following genes, whose expression level in the rash of atopic dermatitis patients is higher than that in healthy subjects: transforming growth factor, beta receptor III (betaglycan, 300kD), BTF3 protein homologue ヽ emogloDin, alpha 1, hemoglobin, beta, alternative activated macrophage specific CC chemokine 1, Pro lact in-Induced Protein N branched chain alph a-ketoacid dehydrogenase kinase ^ type I sigma receptor isoform 1, type I sigma receptor isoform 2, type I sigma receptor isoform 3, type I sigma receptor isoform 4, type I sigma receptor isoform 5, KIAA0664 protein, FK506-binding protein IB isoform a, FK506-binding protein IB isoform b, lymphoid-: restricted membrane protein (L MP), specific granule prote in (28 kDa) (SGP28), ATPase, Ca ++ transporting, ubiquitous ^ general tra ascription factor I IF, polypeptide 2, 30kDa, carboxypeptidase M, tyrosinase-related protein 1, HCR (a- he lix coiled-coil rod homologue), FLJ125 25, A-- gamma glo in ^ complement component 1, q subcomponent, beta polype ptide, SET binding factor 1 (SBF1), hi stidine ammonia-lyase, KIM0440, ES is, Moderately simi lar to 2004399A chromosomal protein ^ gap junction protein, beta 3, 31kD (connexin 31), androgen-regulated short-chain dehydrogenase / reductase 1, nuclear receptor subfamily 1, group H, member 2, matrilysin (MMP7), and runt-related transcription factor 1
d) 以下の遺伝子からなる、 アトピー性皮膚炎患者の無疹部における発現レべ ルが健常者の発現レベルに比べて低い指標遺伝子群： junD、 c-jun proto oncog ene、 c一 fos、 G0S3/Fos— B、 c-myc oncogene^ jun - B、 ATF3 ^activating trans cr iption factor 3)、 AREB6、 ETR101、 ZFP36 (zinc finger protein 36)、 ets - 2、 EZF、 MITF (microphthalmia - associated transcription factor) » EGRl (early growth response 1)、 EGR2 (early growth response 2)、 BTG2、 画- 3、 Idl、 Id2、 Id3、 TR3 (nuclear receptor subfamily 4， group A, member 1)、 NOT (n uclear receptor subfamily 4, group A, member 2)、 CL 100/dual specif icit y phosphatase 1、 cyclooxygenase-2 (hCox - 2)、 cytochrome P450 4F2 (CYP4F 2)、 prostaglandin D2 synthase^ Fatty acid desaturase 1、 Fatty acid desa turase 2、 cholesterol 25-hydroxylases 11-beta-hydroxysteroid dehydrogen ase (HSD11)、 glutamate pyruvate transaminase (GPT)、 glycine decarboxyla se、 ornithine decarboxylase (0DC)、 GADD34/Protein phosphatasel regulato ry subunit 15A、 carboxypeptidase Z、 DKFZp434J214^ Cdk— inhibitor p57KIP2、 WAFl/cyclin - dependent kinase inhibitor 1A (p21, Cipl)、 GEM (GTP binding protein overexpressed in skeletal muscle)、 G0S8/RGS2 (regulator of G-p rotein signalling 2)、 A28 - RGS14p、 BL34/regulator of G - protein signallin g 1、 beta - 2 - adrenergic receptorヽ major group rhinovirus receptor (HRV) / ICAM-1 (CD54) s HB15/CD83、 CD69、 secreted epithelial tumor mucin antigen (MUCl) /CD227、 SLC、 GRO- beta、 amphiregulin (AR)、 heparin- binding EGF-lik e growth factorヽ KIAA0508S DKFZp434A202、 DKFZp564F212s KIAA0924, 画 2 (匪， U2 small nuclear)ヽ RIGUI/PERl (period homolog 1)、 metal lothioneind) An indicator group consisting of the following genes, whose expression level in the eruption area of atopic dermatitis patients is lower than that in healthy subjects: junD, c-jun proto oncogene, c-fos, G0S3 / Fos-B, c-mycocogene ^ jun-B, ATF3 ^ activating trans cription factor 3), AREB6, ETR101, ZFP36 (zinc finger protein 36), ets-2, EZF, MITF (microphthalmia-associated transcription factor) »EGRl (early growth response 1), EGR2 (early growth response 2), BTG2, stroke-3, Idl, Id2, Id3, TR3 (nuclear receptor subfamily 4, group A, member 1), NOT (nuclear receptor subfamily 4 , group A, member 2), CL 100 / dual specif icit y phosphatase 1, cyclooxygenase-2 (hCox-2), cytochrome P450 4F2 (CYP4F 2), prostaglandin D2 synthase ^ Fatty acid desaturase 1, Fatty acid desa turase 2, cholesterol 25-hydroxylase s 11-beta-hydroxysteroid dehydrogenase (HSD11), glutamate pyruvate transaminase (GPT), glycine decarboxyla se, ornithine decarboxylase (0DC), GADD34 / Protein phosphatasel regulatory subunit 15A, carboxypeptidase Z, DKFZp434J214 ^ Cdk— inhibitor p57KIP2, WAFl / cyclin-dependent kinase inhibitor 1A (p21, Cipl), GEM (GTP binding protein overexpressed in skeletal) G0S8 / RGS2 (regulator of GP signaling 2), A28-RGS14p, BL34 / regulator of G-protein signalling g 1, beta-2-adrenergic receptor ヽ major group rhinovirus receptor (HRV) / ICAM-1 (CD54) s HB15 / CD83, CD69, secreted epithelial tumor mucin antigen (MUCl) / CD227, SLC, GRO- beta, amphiregulin (AR), heparin- binding EGF-lik e growth factorヽKIAA0508 S DKFZp434A202, DKFZp564F212 s KIAA0924, picture 2 (wicked person, U2 small nuclear) ヽ RIGUI / PERl (period homolog 1), metal lothionein
2A、 IPL/TSSC3 (tumor suppressing sub transferable candidate 3)、 Wnt inh ibitory factor - 1、 APR (ATL- derived PMA-responsive gene)、 clone 23568, 2 3621, 23795, 23873 and 23874 mRNA、 radiation- inducible immediate-early gene (IEX - 1)ヽ FABP7 (fatty acid binding protein 7, brain) % galaniru clo ne 23933、 glucose transporter-l ike protein - III (GLUT3)、 cytokeratin 15、 CYR61、 IgG Fc binding protein^ GADD45B (growth arrest and DNA- damage - in ducible, beta) , STAT induced STAT inhibitor- 3/S0CS-3、 および tumor necro sis factor alpha inducible protein A20 2A, IPL / TSSC3 (tumor suppressing sub transferable candidate 3), Wnt inh ibitory factor-1, APR (ATL-derived PMA-responsive gene), clone 23568, 2 3621, 23795, 23873 and 23874 mRNA, radiation-inducible immediate- early gene (IEX-1) ヽ FABP7 (fatty acid binding protein 7, brain) % galaniru clo ne 23933, glucose transporter-like protein-III (GLUT3), cytokeratin 15, CYR61, IgG Fc binding protein ^ GADD45B (growth arrest and DNA- damage-in ducible, beta), STAT induced STAT inhibitor-3 / S0CS-3, and tumor necrosis factor alpha inducible protein A20
d' ) 以下の遺伝子からなる、 アトピー性皮膚炎患者の無疹部における発現レ ベルが健常者の発現レベルに比べて低い指標遺伝子群： CL 100 / dual specifi city phosphatase 1ヽ cyclooxygenase - 2 (hCox-2)、 T cell receptor delta lo cus、 chorionic gonadotropin beta subunit、 dual specificity phosphatase 2、 c-jun proto oncogene^ c - fos、 WAFl / cyclin - dependent kinase inhibito r 1A (p21, Cipl)、 weel tyrosine kinase、 jun-B、 prostaglandin D2 synthas e、 pleiotrophin、 TR3 (nuclear receptor subfamily 4， group A, member 1)、 ATF3 (activating transcription factor 3)、 tumor necrosis factor recepto T superfamily, member 13B、 H2B hi stone family, member H、 keratin, hair, acidic, 3A、 37 kDa leucine -： rich repeat (LRR) protein^ cholesterol 25-h ydroxylase^ SMARCD3、 brain abundant, membrane attached signal protein 1、 SEC24 related gene family, member D (S. cerevisiae)、 glutathione S-tran sf erase M3 (brain) N Friedreich ata iaN zinc finger protein 187、 KIAA109 5 protein^ AREB6、 MLLT10、 ESTs (Accession No. AI829701)、 collagen, type XIV, alpha 1 (undulin)、 FLJ12280, araphiregulin (A ) N ESTs (Accession No.d ') An indicator gene group consisting of the following genes, whose expression level in the eruption area of atopic dermatitis patients is lower than that in healthy subjects: CL 100 / dual specifi city phosphatase 1 ヽ cyclooxygenase-2 (hCox -2), T cell receptor delta locus, chorionic gonadotropin beta subunit, dual specificity phosphatase 2, c-jun proto oncogene ^ c-fos, WAFl / cyclin-dependent kinase inhibito r 1A (p21, Cipl), weel tyrosine kinase, jun-B, prostaglandin D2 synthas e, pleiotrophin, TR3 (nuclear receptor subfamily 4, group A, member 1), ATF3 (activating transcription factor 3), tumor necrosis factor recepto T superfamily, member 13B, H2B hi stone family, member H , Keratin, hair, acidic, 3A, 37 kDa leucine-: rich repeat (LRR) protein ^ cholesterol 25-h ydroxylase ^ SMARCD3, brain abundant, membrane attached signal protein 1, SEC24 related gene family, member D (S. cerevisiae) , Glutathione S-tran sf erase M3 (brain) N Friedr eich ata ia N zinc finger protein 187, KIAA109 5 protein ^ AREB6, MLLT10, ESTs (Accession No.AI829701), collagen, type XIV, alpha 1 (undulin), FLJ12280, araphiregulin (A) N ESTs (Accession No.
AC004940)、 molybdenum cofactor synthesis 3、 guanylate binding protein 1， interferon-inducible, 67kDa、 ras homo log gene family, member E、 KIM 0924、 armadillo repeat protein ALEX2、 ETR101、 MIP -ト alpha、 caspase 3, a poptos is - related cysteine protease (variant beta)、 caspase 3, apoptosi s - related cysteine protease (variant alpha)、 clone 23933、 keratin, hair, acidic, 1、 BL34 I regulator of G- protein signalling 1、 Idl、 BTG2、 G0S3
Figure imgf000356_0001
AC004940), molybdenum cofactor synthesis 3, guanylate binding protein 1, interferon-inducible, 67kDa, ras homo log gene family, member E, KIM0924, armadillo repeat protein ALEX2, ETR101, MIP-alpha, caspase 3, a poptos is- related cysteine protease (variant beta), caspase 3, apoptosis-related cysteine protease (variant alpha), clone 23933, keratin, hair, acidic, 1, BL34 I regulator of G-protein signaling 1, Idl, BTG2, G0S3
Figure imgf000356_0001
I Fos- B、 weel tyrosine kinase^ glucose transporter-like protein - III (G LUT3)、 YDD19 protein GRO- beta、 serine (or cysteine) proteinase inhibit or, clade I (neuroserpin) , member 1、 GEM (GTP binding protein overexpre ssed in skeletal muscle)、 HB15 / CD83、 N0T、 CD95, FAS、 CD69、 c-rayc onco gene、 holocarboxylase synthetase^ zinc finger protein 337、 chromosome c ondensation 1、 heparin-binding EGF - like growth factor^ dermatopontin^ S ERPINE1、 interleukin 6 (interferon, beta 2)、 Prostag andin D2 Synthetas e 21kD (brain)、 zinc finger protein 36, C3H type-like 1、 CYR61、 IgG Fc binding protein^ protein phosphatase 5, catalytic subunit、 P311 protein^ GADD45B (growth arrest and DNA- damage - inducible, beta) N ADP -： ribosylatio n factor-like 7、 syntaxin 11、 ZFP36 (zinc finger protein 36)、 NDRG fami 丄 y member 4、 APR (ATL - derived PMA— responsive gene) T54 protein^ A28-RG ύΐ4ρ、 rearranged L-myc fusion sequence、 clone 24790、 nuclear receptor s ubfamily 4, group A, member 2、 tumor necrosis factor alpha inducible pr otein A20、 beta— 2 - adrenergic receptor^ phosphodiesterase 3B、 EGRl (earl y growth response 1)、 および MCPl I Fos-B, weel tyrosine kinase ^ glucose transporter-like protein-III (G LUT3), YDD19 protein GRO-beta, serine (or cysteine) proteinase inhibit or, clade I (neuroserpin), member 1, GEM (GTP binding protein overexpre ssed in skeletal muscle), HB15 / CD83, N0T, CD95, FAS, CD69, c-rayc onco gene, holocarboxylase synthetase ^ zinc finger protein 337, chromosome condensation 1, heparin-binding EGF-like growth factor ^ dermatopontin ^ S ERPINE1, interleukin 6 (interferon, beta 2), Prostag andin D2 Synthetas e 21kD (brain), zinc finger protein 36, C3H type-like 1, CYR61, IgG Fc binding protein ^ protein phosphatase 5, catalytic subunit, P311 protein ^ GADD45B (growth arrest and DNA- damage-inducible, beta) N ADP-: ribosylatio n factor-like 7, syntaxin 11, ZFP36 (zinc finger protein 36), NDRG fami 丄 y member 4, APR (ATL-derived PMA- responsive gene ) T54 protein ^ A28-RG ύΐ4ρ, rearranged L-myc fusion sequence, clone 24790, nuclear receptor s ubfamily 4, group A, member 2, tumor necrosis factor alpha inducible protein A20, beta—2-adrenergic receptor ^ phosphodiesterase 3B, EGRl (early growth response 1), and MCPl
2 . a)の指標遺伝子群力 S、 metal loproteinase (羅)、 type IV collagenase、 c athepsin Z precursor (CTSZ)、 disintegrin-protease^ pro-cathepsin L (m ajor excreted protein MEP)、 skin collagenaseN SPUVE (protease, serine,2.A) Index gene group power S, metal loproteinase (Ra), type IV collagenase, cathepsin Z precursor (CTSZ), disintegrin-protease ^ pro-cathepsin L (major excreted protein MEP), skin collagenase N SPUVE ( protease, serine,
23)、 Proprotein convertase subtilisin/kexin typel、 tissue inhibitor of metalloproteinasesN beta-migrating plasminogen activator inhibitor23), Proprotein convertase subtilisin / kexin typel, tissue inhibitor of metalloproteinases N beta-migrating plasminogen activator inhibitor
I、 IL— 13Ral、 IFN— beta 2a (IL— 6)、 heparin-binding EGF- like growth fa ctor, GM-CSFR beta, interleukin 8 (IL8)、 MCP— 1、 EBIl-ligand cheraokine, SLC、 GRO - beta、 monocyte chemotactic protein - 2、 CCR1、 lymph node homin g receptor / L~selectin endothelial leukocyte adhesion molecule 1 (E LAM— 1)、 leukocyte adhesion protein (LFA-l/Mac-l/pl50, 95 fami丄 yノ beta、 TNFAIP6 (tumor necrosis factor, alpha-induced protein 6)、 M130 antige n extracellular variant / CD163、 CD53 glycoprotein^ T200 leukocyte co nunon antigen (CD45, LC-A) isoform 1-3、 THY - 1 (CD90)、 leucocyte immuno globulin-like receptor- 3 (LIR-3) tenascin- C、 alpha - 1 type XV collage n、 cartilage oligomeric matrix protein (C0MP)、 proteoglycan 1、 immuno globulin lambda light chainゝ Fc-epsi Ion - receptor gamma - chainゝ IgG low affinity Fc fragment receptor (CD32)、 immunoglobulin heavy constant gamma 3 (G3m marker)、 immunoglobulin kappa constant^ hemopoietic cell protein-tyrosine kinase (HCK)、 KIAA0687 / MAP4K4、 ornithine decarbox ylase ODC (EC 4. 1. 1. 17)、 phospholipase A2， group IIA (platelets, syno vial fluid)ゝ nicotinamide N-methyltransf erase (NNMT)、 actin related p rotein 2/3 complex, subunit IB (41 kD)ヽ myosin IB、 gamma- interferon- i nducible protein (IP- 30)、 RAB31、 regulator of G- protein signalling 1 (BL34) N TNRC3、 insulin-like growth factor binding protein 4 (IGFBP4)、 nel- related protein 2、 neuronal "tissue - enriched acidic protein (NAP— 2 2)、 DKFZp58600118 / KI 1199、 lysosomal- associated multitransmembrane protein (LAPTni5)ゝ KI 0296、 serum amyloid Al、 TYRO protein tyrosine kinase binding protein^ fatty acid binding protein homologue (PA-FAB P)、 fibrinogen - like 2、 およぴ six transmembrane epithelial antigen of the prostate (STEAP)から選択されたいずれかの遺伝子である請求項 1に記 載の方法。 I, IL-13Ral, IFN-beta 2a (IL-6), heparin-binding EGF- like growth factor, GM-CSFR beta, interleukin 8 (IL8), MCP-1, EBIl-ligand cheraokine, SLC, GRO- beta, monocyte chemotactic protein-2, CCR1, lymph node homin g receptor / L ~ selectin endothelial leukocyte adhesion molecule 1 (E LAM-1), leukocyte adhesion protein (LFA-l / Mac-l / pl50, 95 fami 丄 y) beta, TNFAIP6 (tumor necrosis factor, alpha-induced protein 6), M130 antigen extracellular variant / CD163, CD53 glycoprotein ^ T200 leukocyte co nunon antigen (CD45, LC-A) isoform 1-3, THY-1 (CD90), leucocyte immuno globulin-like receptor- 3 (LIR-3) tenascin- C, alpha-1 type XV collagen, cartilage oligomeric matrix protein (C0MP), proteoglycan 1, immuno globulin lambda light chain ゝ Fc-epsi Ion-receptor gamma-chain ゝIgG low affinity Fc fragment receptor (CD32), immunoglobulin heavy constant gamma 3 (G3m marker), immunoglobulin kappa constant ^ hemopoietic cell protein-tyrosine kinase (HCK), KIAA0687 / MAP4K4, ornithine decarbox ylase ODC (EC 4.1.1. 17), phospholipase A2, group IIA (platelets, syno vial fluid) ゝ nicotinamide N-methyltransf erase (NNMT), actin related protein 2/3 complex, subunit IB (41 kD) ヽ myosin IB, gamma-interferon-inducible protein (IP-30), RAB31, regulator of G- protein signaling 1 (BL34) N TNRC3, insulin-like growth factor binding protein 4 (IGFBP4), nel-related protein 2, neuronal `` tissue-enriched acidic protein (NAP-2 2), DKFZp58600118 / KI 1199, lysosomal-associated multitransmembrane protein (LAPTni5) ゝ KI 0296, serum amyloid Al, TYRO protein tyrosine kinase binding protein ^ fatty acid binding protein homologue (PA-FAB P), fibrinogen-like 2, and six transmembrane epithelial antigen of the prostate (STEAP). The method described in.
. a)の指標遺 子群カヽ cathepsin Cゝ airway "trypsin- like proteaseゝ ser ine protease-like protein、 protease M、 trypsinogen IV b-form^ neutrop hil gelatinase associated lipocalin、 squamous cell carcinoma antigen: serine protease inhibitor N squamous cell carcinoma antigen 2 (SCCA2)、 mononcyte/neutrophi丄 elastase inhibitor λ alpha 1一 antitrypsin elafinゝ
Figure imgf000358_0001
Indices of group a) cathepsin C ゝ airway `` trypsin- like protease ゝ serine protease-like protein, protease M, trypsinogen IV b-form ^ neutrop hil gelatinase associated lipocalin, squamous cell carcinoma antigen: serine protease inhibitor N squamous cell carcinoma antigen 2 (SCCA2), mononcyte / neutrophi 丄 elastase inhibitor λ alpha 1 antitrypsin elafin ゝ
Figure imgf000358_0001
interleukin-7 receptor ^ interleukin 4 receptor platelet-derived endo t elial cell growth f actor pre- B cell enhancing factor (PBEF)、 alter native activated macrophage specific CC chemokine 1、 lactotransferrin^ melanoma growth stimulatory activity (MGSA) / Gro alpha、 psoriasin (S 100A7)、 MRP- 8 (S100A8)、 MRP- 14 (S100A9)、 CaN19 (S100A2)、 p cadherin, 13 0-kD pemphigus vulgaris antigen I Desmoglein 3、 desmocol l ins type 2b、 CD24 signal transducer^ 0A3 antigenic surface determinant / CD47、 mon ocyte/macrophage . Ig-related receptor MIR- 7 / CD85、 lyn、 protein tyros ine phosphatase, receptor type, E i soforml，2、 tartrate— res istant acid phosphatase type 5、 cholesterol 25-hydroxylase^ Phospholipid scrambl ase 1、 manganese superoxide dismutase (EC 1. 15. 1. 1)、 uridine phosphor yiase、 aldose reductase - l ike peptide^ 2' , 5' ol igoadenylate synthetase isoform E16, £18、 2，， 5， oligoadenylate synthetase 2 isoform p69, p71、 L-kynurenine hydrolase^ purine nucleoside phosphorylase (PNP ; EC 2. 4. 2· 1)、 2， , 5， oligoadenylate synthetase- like (59 kDa isoform)、 cytokera tin 17、 kerat in 6A、 keratin 16、 myosin VA (heavy polypeptide 12, myox inノ、 Small proline -; rich protein SPRK、 small proline - rich protein 2kヽ small proline -; rich protein IB (cornifin)、 involucrin^ interferon - indu c ib丄 e protein p78 (MX1)、 interferon - induced 17 - kDa/15- kDa protein^ p2 7, interferon - alpha - inducible protein 27、 regulator of G - protein s ign ailing 20、 STAT1、 cyclin B、 proto - oncogene (Wnt - 5a)、 beta defensin 2 (腦 2)、 KIAA0101, tumor suppressing subtransferable candidate 3 (TSSC 3)、 heparin binding protein (HBpl 7) / FGF-BP1、 および trans cobalamin I から選択されたいずれかの遺伝子である請求項 1に記載の方法。 interleukin-7 receptor ^ interleukin 4 receptor platelet-derived endo t eial cell growth f actor pre- B cell enhancing factor (PBEF), alter native activated macrophage specific CC chemokine 1, lactotransferrin ^ melanoma growth stimulatory activity (MGSA) / Gro alpha, psoriasin (S 100A7), MRP-8 (S100A8), MRP-14 (S100A9), CaN19 (S100A2), p cadherin, 130-kD pemphigus vulgaris antigen I Desmoglein 3, desmocolins type 2b, CD24 signal transducer ^ 0A3 antigenic surface determinant / CD47, monocyte / macrophage.Ig-related receptor MIR-7 / CD85, lyn, protein tyros ine phosphatase, receptor type, Eisoforml, 2, tartrate- res istant acid phosphatase type 5, cholesterol 25-hydroxylase ^ Phospholipid scramblase 1, manganese superoxide dismutase (EC 1.15.1.1), uridine phosphor yiase, aldose reductase-like peptide ^ 2 ', 5' ol igoadenylate synthetase isoform E16, £ 18, 2, 5, oligoadenylate synthetase 2 isoform p69, p71, L-kynurenine hydro lase ^ purine nucleoside phosphorylase (PNP; EC 2.4.2.1), 2,, 5, oligoadenylate synthetase-like (59 kDa isoform), cytokera tin 17, kerat in 6A, keratin 16, myosin VA (heavy polypeptide 12) , myox inno, Small proline-; rich protein SPRK, small proline-rich protein 2k ヽ small proline-; rich protein IB (cornifin), involucrin ^ interferon-indu c ib 丄 e protein p78 (MX1), interferon-induced 17 -kDa / 15- kDa protein ^ p2 7, interferon-alpha-inducible protein 27, regulator of G-protein s ign ailing 20, STAT1, cyclin B, proto-oncogene (Wnt-5a), beta defensin 2 (brain 2) The method according to claim 1, which is any gene selected from KIAA0101, tumor suppressing subtransferable candidate 3 (TSSC 3), heparin binding protein (HBpl 7) / FGF-BP1, and trans cobalamin I.
. b)の指標遺伝子群が、 cathepsin V、 SERPINB7 (s erine (or cysteine) pro teinas e inhi itor, clade B (ovalbumin) , member 7)、 cytokeratin 15、 de sminN extracellular matrix protein 2、 KIM0537、 deoxyribonuclease I一 1 ike 2 (DNAS1L2) phosphoenolpyruvate carboxykinase (PCK1)、 3 - hydroxy- 3-methylglutaryl coenzyme A synthase^ arylacetamide deacet iase、 ATPa se, Cu++ transporting, alpha polypeptide (ATP7A)ゝ tyrosinase (TYR)、 m onoamine oxidase A、 Aldehyde dehydrogenase 5 family, member Al、 alcoh ol dehydrogenase 1A (class 1)， alpha polypeptide^ alcohol dehydrogena se 1C (class I) , gamma polypeptide^ degenerative spermatocyte homo log (sphingolipid delta 4 desaturase) a丄 pha - 2—glycoprotein 1， zincゝ per ilipin、 lipoprotein 丄 ipase、 aldehyde dehydrogenase 3 family, member A 2、 Hemoglobin alpha 1， alpha 2 chain、 class I homeoprotein (H0XA9)、 p romyelocytic leukemia zinc finger protein (PLZF)、 calcium channel, vo ltage - dependent, alpha 1H subunit、 sodium channel, nonvoltage-gated 1， beta、 LIGl (ortholog of mouse integral membrane glycoprotein LIG-1)、 WFSl (Wolfram syndrome 1)、 progesterone receptor membrane component 2、 peanut-like 1 (Drosophila) type 1 angiotensin II receptor, variant 1 - 5、 EphB6、 betacellulin、 proline rich 4 (lacrimal)、 retinol binding protein 4、 DKFZP434G0310 (hypothetical protein) N loricrin DKFZp586H2 123、 KIAA0624, DKFZp564D206, および DKFZP586F1223から選択されたいずれ かの遺伝子である請求項 1に記載の方法。The indicator genes of b) are cathepsin V, SERPINB7 (serine (or cysteine) pro teinas e inhi itor, clade B (ovalbumin), member 7), cytokeratin 15, de smin N extracellular matrix protein 2, KIM0537, deoxyribonuclease I-1 ike 2 (DNAS1L2) phosphoenolpyruvate carboxykinase (PCK1), 3-hydroxy-3-methylglutaryl coenzyme A synthase ^ arylacetamide deacet iase, ATPa se, Cu ++ transporting, alpha polypeptide (ATP7A)ゝ tyrosinase (TYR), monoamine oxidase A, Aldehyde dehydrogenase 5 family, member Al, alcohol dehydrogenase 1A (class 1), alpha polypeptide ^ alcohol dehydrogena se 1C (class I), gamma polypeptide ^ degenerative spermatocyte homo log (sphingolipid delta 4 desaturase) a 丄 pha-2-glycoprotein 1, zinc ゝ per ilipin, lipoprotein 丄 ipase, aldehyde dehydrogenase 3 family, member A 2, Hemoglobin alpha 1, alpha 2 chain, class I homeoprotein (H0XA9), promyelocytic leukemia zinc finger protein (PLZF), calcium channel, volume-dependent, alpha 1H subunit, sodium channel, nonvoltage-gated 1, beta, LIGl (ortholog of mouse integral membrane glycoprotein LIG-1), WFSl (Wolfram syndrome 1), p rogesterone receptor membrane component 2, peanut-like 1 (Drosophila) type 1 angiotensin II receptor, variant 1-5, EphB6, betacellulin, proline rich 4 (lacrimal), retinol binding protein 4, DKFZP434G0310 (hypothetical protein) N loricrin DKFZp586H2 123, KIAA0624, DKFZp564D206, and DKFZ method according to claim 1 from P 586F1223 is any Kano genes selected.
. b)の指標遺伝子群が、 kallikreinl、 cystatin E/M、 tissue inhibitor of metal loproteinase 4、 KIAA1775 (MT-protocadherin) N keratin 18、 keratin 19、 smooth muscle myosin heavy chain 11， isoform SM2、 sciellin (SCE し)、 KIAA0353 I desmus丄 in (intermediate filament protein)、 calponinl、 protein- tyrosine - phosphatase Dl、 angiogenin (RNase A family, 5)、 RNa se , carbonic anhydrase isozyme VI (CA6)、 amylase, alpha 2B; pancrea tic、 CMP-N-acetylneuraminic acid hydroxylase^ Aminomethyl transferase 3 5 ' —_」. The indicator genes of b) are kallikreinl, cystatin E / M, tissue inhibitor of metal loproteinase 4, KIAA1775 (MT-protocadherin) N keratin 18, keratin 19, smooth muscle myosin heavy chain 11, isoform SM2, sciellin (SCE ), KIAA0353 I desmus 丄 in (intermediate filament protein), calponinl, protein-tyrosine-phosphatase Dl, angiogenin (RNase A family, 5), RNase, carbonic anhydrase isozyme VI (CA6), amylase, alpha 2B; pancrea tic, CMP-N-acetylneuraminic acid hydroxylase ^ Aminomethyl transferase 3 5 '—_''.
(glycine cleavage system protein T)ヽ Cytochrome P450, subfami ly IIIA, polypeptide 5、 alcohol dehydrogenase IB (class I) , beta polypeptide^ FABP7 (fatty acid binding protein 7)、 FABP4 (Fatty acid binding prote in 4)、 KIAA0273 / phytanoyl-CoA hydroxylase interacting protein^ apol ipoprotein D、 apolipoprotein E、 hemoglobin, gamma A, gamma G、 hemoglo bin, beta、 mammaglobm 1、 ma丽 aglobin 2、 secretoglobin, family ID, rae mber 2、 elta sleep inducing peptide, immunoreactorN beta - catenin - int eracting protein ICAT、 GATA3、 forkhead/winged helix - like transcript io n factor 7 (FKHL7) Inhibitor of DNA binding 4 (ID4)、 Beta-microsemin oprotein isoform a (PSP94) , isoform b (PSP57) Λ testicular inhibin bet a - B- subunit、 TM4SF3 (transmembrane 4 superfamily member 3)、 ITM2A (in tegral membrane protein 2A)、 claudin 8、 syndecan 4 (amphiglycan, ryud ocan)、 proteolipid protein 1、 apMl (adipose most abundant gene transcr ipt 1)、 prolactin-inducible proteinヽ HZF9、 skin-specific protein (xp3 2)、 Crystallin, alpha B、 Hepatocellular carcinoma antigen gene 520、 P urkinje cell protein 4 (PCP4)、 141H5、 cyclin Dl、 TRIM2 (tripartite mo tif - containing 2)、 metallothionein IV (MTIV)、 transmembrane 4 superfa mily member 11 (plasmolipin) , DKFZp434A202、 KIAA0471 KIAA0450、 KIAAO 633、 KIAA0456, Clorf21、 および DKFZp761F2014から選択されたいずれかの 遺伝子である請求項 1に記載の方法。 (glycine cleavage system protein T) ヽ Cytochrome P450, subfamily IIIA, polypeptide 5, alcohol dehydrogenase IB (class I), beta polypeptide ^ FABP7 (fatty acid binding protein 7), FABP4 (Fatty acid binding prote in 4), KIAA0273 / phytanoyl-CoA hydroxylase interacting protein ^ apol ipoprotein D, apolipoprotein E, hemoglobin, gamma A, gamma G, hemoglo bin, beta, mammaglobm 1, ma 丽 aglobin 2, secretoglobin, family ID, rae mber 2, elta sleep inducing peptide, immunoreactor N beta-catenin-int eracting protein ICAT, GATA3, forkhead / winged helix-like transcript ion factor 7 (FKHL7) Inhibitor of DNA binding 4 (ID4), Beta-microsemin oprotein isoform a (PSP94), isoform b (PSP57) Λ testicular inhibin bet a - B- subunit , TM4SF3 (transmembrane 4 superfamily member 3), ITM2A (in tegral membrane protein 2A), claudin 8, syndecan 4 (amphiglycan, ryud ocan), proteolipid protein 1, apMl (adipose most abundant gene transcr ipt 1), prolactin-inducible prot ein ヽ HZF9, skin-specific protein (xp3 2), Crystallin, alpha B, Hepatocellular carcinoma antigen gene 520, Purkinje cell protein 4 (PCP4), 141H5, cyclin Dl, TRIM2 (tripartite mo tif-containing 2), metallothionein IV The method according to claim 1, wherein the gene is any one selected from (MTIV), transmembrane 4 superfamily member 11 (plasmolipin), DKFZp434A202, KIAA0471 KIAA0450, KIAAO 633, KIAA0456, Clorf21, and DKFZp761F2014.
. c )の 遺 is子群力 BTF3 protein homologue、 general transcription I actor I IF, polypeptide 2， 30kDas alternative activated macrophage sp ecific CC chemokine 1、 complement component 1， q subcomponent, beta p olypeptide% transforming growth factor, beta receptor III (betaglycan,c) is islet group power BTF3 protein homologue, general transcription I actor I IF, polypeptide 2, 30kDa s alternative activated macrophage sp ecific CC chemokine 1, complement component 1, q subcomponent, beta polypeptide % transforming growth factor, beta receptor III (betaglycan,
300 D) branched chain alpha-ketoacid dehydrogenase kinaseヽ ATPase, Ca++ transporting, ubiquitous^ tyrosinase -: related protein 1、 histidin
Figure imgf000361_0001
300 D) branched chain alpha-ketoacid dehydrogenase kinase ヽ ATPase, Ca ++ transporting, ubiquitous ^ tyrosinase-: related protein 1, histidin
Figure imgf000361_0001
e a墮 onia - lyase、 androgen - regulated short-chain dehydrogenase/ r educta se 1、 gap junction protein, beta 3， 31kD (connexin 31)、 KI 0440、 lym phoid- restricted membrane protein (LRMP)、 matrilysin (騰 7)、 specific granule protein (28 kDa) (SGP28) type I sigma receptor^ FK506 bindi ng protein IB, 12. 6 kDa Prolactin— Induced Protein^ SET binding facto r 1 (SBF1)、 および FLJ12525力 ら選択されたいずれかの遺伝子である請求項ea corrupt onia-lyase, androgen-regulated short-chain dehydrogenase / reductase 1, gap junction protein, beta 3, 31kD (connexin 31), KI 0440, lym phoid-restricted membrane protein (LRMP), matrilysin (rise 7) , Specific granule protein (28 kDa) (SGP28) type I sigma receptor ^ FK506 bindin ng protein IB, 12.6 kDa Prolactin-- Induced Protein ^ SET binding factor 1 (SBF1), and one selected from FLJ12525 Claims that are genes
1に記載の方法。The method according to 1.
. c， )の指標 伝子群;^、, hemoglobin, alpha 1、 sickle cell beta-glob ϊη beta-globin (HBB)、 A - gamma globin、 carboxypeptidase M、 HCR (a - helix c oiled-coil rod homo丄 ogue)、 nuclear receptor subfamily 1, group H, mem ber 2、 ESTs, Moderately similar to 2004399A chromosomal protein^ run t— related transcription factor 1、 およぴ KI 0664 proteinから選択され たいずれかの遺伝子である請求項 1に記載の方法。c,) Index Genes; ^ ,, hemoglobin, alpha 1, sickle cell beta-glob ϊη beta-globin (HBB), A-gamma globin, carboxypeptidase M, HCR (a-helix c oiled-coil rod homo Ogue), nuclear receptor subfamily 1, group H, membrane 2, ESTs, Moderately similar to 2004399A chromosomal protein ^ run t—related transcription factor 1, and KI 0664 protein Item 1. The method according to item 1.
. d' )の指標遺伝子群が、 Idl、 BTG2、 zinc finger protein 36, C3H type-li ke 1、 EGRl (eariy growth response 1)、 MIP— 1 - alpha、 MCP1、 tumor necros is factor receptor superfamily, member 13B、 HB15 / CD83、 CD95, FAS、 C D69、 T cell receptor delta 丄 ocus、 caspase 3, apoptosis—: related cystei ne protease^ serine (or cysteine) proteinase inhibitor, clade I (neur oserpin) , member 1、 SERPI E1、 prostaglandin D2 synthase 21 kDa (brain)、 cholesterol 25 - hydroxylase、 glutathione S - transferase M3 (brain) pro tein phosphatase 5， catalytic subunit、 phosphodiesterase 3B、 regulato r of G— protein signalling 16、 heparin— binding EGF - like growth factor、 pleiotrophin^ weel tyrosine kinase^ SMARCD3、 IgG Fc binding protein^ chorionic gonadotropin beta subunitN keratin, hair, acidic, 3A、 37 kD a leucine -: rich repeat (LRR) protein^ brain abundant, membrane attache d signal protein 1、 SEC24 related gene family, member D (S. cerevisia e)、 Friedreich ataxia^ zinc finger protein 187、 zinc finger protein 3 37、 MLLT10、 collagen, type XIV, alpha 1 (undulin)、 molybdenum cofacto r synthesis 3、 guanylate binding protein 1， interferon-inducible, 67k Da、 ras homo log gene family, member E、 armadillo repeat protein ALEX2、 keratin, hair, acidic, 1、 YDD19 protein^ chromosome condensation 1、 d ermatopontinN P311 protein^ syntaxin 11、 NDRG family member 4、 rearra nged L-myc fusion sequence^ clone 24790、 KIM1095 protein^ FLJ12280、 ESTs (Accession No. AC004940)、 およぴ ESTs (Accession No. AI829701)から 選択されたいずれかの遺伝子である請求項 1に記載の方法。d ') are Idl, BTG2, zinc finger protein 36, C3H type-like 1, EGRl (eariy growth response 1), MIP-1-alpha, MCP1, tumor necros is factor receptor superfamily, member 13B, HB15 / CD83, CD95, FAS, CD69, T cell receptor delta 丄 ocus, caspase 3, apoptosis—: related cystei ne protease ^ serine (or cysteine) proteinase inhibitor, clade I (neur oserpin), member 1, SERPI E1, prostaglandin D2 synthase 21 kDa (brain), cholesterol 25-hydroxylase, glutathione S-transferase M3 (brain) pro tein phosphatase 5, catalytic subunit, phosphodiesterase 3B, regulator of G—protein signaling 16, heparin—binding EGF-like growth factor, pleiotrophin ^ weel tyrosine kinase ^ SMARCD3, IgG Fc binding protein ^ chorionic gonadotropin beta subunit N keratin, hair, acidic, 3A, 37 kD a leucine-: rich repeat (LRR) protein ^ brain abundant, membrane attache d signal protein 1, SEC24 related gene family, member D (S. cerevisia e), Friedreich ataxia ^ zinc finger protein 187, zinc finger protein 337, MLLT10, collagen, type XIV, alpha 1 (undulin), molybdenum cofactor synthesis 3, guanylate binding protein 1, interferon-inducible, 67k Da, ras homo log gene family, member E, armadillo repeat protein ALEX2, keratin, hair, acidic, 1, YDD19 protein ^ chromosome condensation 1, dermatopontin N P311 protein ^ syntaxin 11, NDRG family member 4, rearra nged L-myc fusion sequence ^ clone 2. The method according to claim 1, wherein the gene is any one selected from 24790, KIM1095 protein ^ FLJ12280, ESTs (Accession No. AC004940), and ESTs (Accession No. AI829701).
. d，）の指標遺伝子群が、 c-jun proto oncogene^ jun- B、 c- fos、 G0S3 / Fo s - B、 c-myc oncogene^ AREBb、 ATF3 (activating transcription factor 3)、 ETR101、 ZFP36 (zinc finger protein 36)、 GRO- beta、 WAFl / cyclin-depen dent kinase inhibitor 1A (p21, し ipl)、 interleukin 6 (interferon, betad,) are c-jun proto oncogene ^ jun-B, c-fos, G0S3 / Fos-B, c-myc oncogene ^ AREBb, ATF3 (activating transcription factor 3), ETR101, ZFP36 ( zinc finger protein 36), GRO-beta, WAFl / cyclin-dependent kinase inhibitor 1A (p21, sipl), interleukin 6 (interferon, beta
2)、 CL 100 I dual specificity phosphatase 1、 c y c 1 oo ygenas e-2 (hCox - 2)、 dual specificity phosphatase 2、 holocarboxylase synthetase^ beta - 2— adrenergic receptor BL34 I regulator of G— protein signalling 1、 GE M (GTP binding protein overexpressed in skeletal muscle 、 amphireguli n (AR)、 nuclear receptor subfamily 4, group A, member 2、 TR3 (nuclear receptor subfamily 4， group A, member 1)、 N0T、 glucose transporter - li ke protein - III (GLUT3)、' GADD45B (growth arrest and DNA - damage - indue ib le, beta) tumor necrosis factor alpha inducible protein A20、 CYR61、 APR (ATL— derived PMA- responsive gene)、 ADP-ribosylation factor-like ΐ T54 protein, H2B histone family, member H、 clone 23933、 および KIAA092 から選択されたいずれかの遺伝子である請求項 1に記載の方法。 2), CL 100 I dual specificity phosphatase 1, cyc 1 oo ygenas e-2 (hCox-2), dual specificity phosphatase 2, holocarboxylase synthetase ^ beta-2—adrenergic receptor BL34 I regulator of G—protein signaling 1, GE M (GTP binding protein overexpressed in skeletal muscle, amphiregulin (AR), nuclear receptor subfamily 4, group A, member 2, TR3 (nuclear receptor subfamily 4, group A, member 1), N0T, glucose transporter-liquid protein-III (GLUT3), 'GADD45B (growth arrest and DNA-damage-indue ib le, beta) tumor necrosis factor alpha inducible protein A20, CYR61, APR (ATL-- derived PMA-responsive gene), ADP-ribosylation factor-like ΐ T54 protein The method according to claim 1, wherein the gene is any one selected from H2B, H2B histone family, member H, clone 23933, and KIAA092.
0 . 遺伝子の発現レベルを、 cDNAの PCRによって測定する請求項 1に記載の 検査方法。 0. The test method according to claim 1, wherein the expression level of the gene is measured by cDNA PCR.
1. 遺伝子の発現レベルを、 指標遺伝子によってコードされる蛋白質の検出に よつて測定する請求項 1に記載の検査方法。1. The test method according to claim 1, wherein the expression level of the gene is measured by detecting a protein encoded by the indicator gene.
2. 指標遺伝子の塩基配列を含むポリヌクレオチド、 またはその相補鎖に相 補的な塩基配列を有する少なくとも 1 5塩基の長さを有するオリゴヌクレオ チドからなる、 アトピー性皮膚炎検査用試薬であって、 指標遺伝子が請求項 1における a)〜 、 並びに c')および d')のいずれかに記載の群から選択され たいずれかの遺伝子であるアトピー性皮膚炎検査用試薬。 2. A reagent for testing atopic dermatitis, comprising a polynucleotide containing the nucleotide sequence of the indicator gene or an oligonucleotide having a length of at least 15 bases and having a complementary nucleotide sequence to its complementary strand. A reagent for testing atopic dermatitis, wherein the indicator gene is any one selected from the group described in any of a) to c) and c ′) and d ′) in claim 1.
3. 指標遺伝子によってコードされる蛋白質を認識する抗体からなる、 アト ピー性皮膚炎検査用試薬であって、 指標遺伝子が請求項 1における a)〜d)、 並びに c')および d，）のいずれかに記載の群から選択されたいずれかの遺伝子 であるアトピー性皮膚炎検査用試薬。 3. An atopic dermatitis test reagent comprising an antibody that recognizes a protein encoded by an indicator gene, wherein the indicator gene is a) to d), and c ′) and d,) according to claim 1. A reagent for testing atopic dermatitis, which is any gene selected from the group described in any of the above.
4. 次の工程を含む、 アトピー性皮膚炎の治療薬のスクリーニング方法であ つて、 指標遺伝子が請求項 1における 〜 d)、 並びに c')および d')のいずれ かに記載の群から選択されたいずれかの遺伝子であるスクリ一ユング方法。 4. A method for screening for a therapeutic agent for atopic dermatitis, comprising the following steps, wherein the indicator gene is selected from the group according to claim 1 to d) and any one of c ′) and d ′): Screened Jung's method, which is any of the genes described above.
(1) 指標遺伝子を発現する細胞に候補化合物を接触させる工程、 (1) contacting a candidate compound with cells expressing the indicator gene,
(2) 前記遺伝子の発現レベルを測定する工程、  (2) measuring the expression level of the gene,
(3) 候補化合物を接触させない対照と比較して、 a)群、 c)群、 および c )群 のいずれかの指標遺伝子については前記遺伝子の発現レベルを低下させる化 合物を、 また b)群、 d)群、 および d')群のいずれかの指標遺伝子については 前記遺伝子の発現レベルを上昇させる化合物を選択する工程  (3) a compound that reduces the expression level of any of the indicator genes of groups a), c) and c) as compared to a control not contacted with the candidate compound; and b) Selecting a compound that increases the expression level of the indicator gene of any of the group, d) group, and d ′) group
5. 細胞が株化皮膚細胞である請求項 14に記載の方法。  5. The method according to claim 14, wherein the cells are established skin cells.
6. 指標遺伝子の塩基配列を含むポリヌクレオチド、 またはその相補鎖に相 補的な塩基配列を有する少なくとも 1 5塩基の長さを有するオリゴヌクレオ チドと、 指標遺伝子を発現する細胞を含む、 アトピー性皮膚炎の治療薬候補 化合物をスクリーニングするためのキットであって、 指標遺伝子が請求項 1 における a；)〜 d)、 並びに c')および d')のいずれかに記載の群から選択された
Figure imgf000364_0001
6. Atopy, including a polynucleotide containing the nucleotide sequence of the indicator gene or an oligonucleotide having a nucleotide sequence complementary to the complementary strand thereof and having a length of at least 15 nucleotides, and a cell expressing the indicator gene A kit for screening a candidate compound for a therapeutic agent for dermatitis, wherein the indicator gene is selected from the group according to any one of a;) to d), and c ′) and d ′) according to claim 1.
Figure imgf000364_0001
いずれかの遺伝子であるキット。  A kit that is any gene.
1 7 . 指標遺伝子によってコードされる蛋白質を認識する抗体と、 指標遺伝子 を発現する細胞を含む、 アトピー性皮膚炎の治療薬候捕化合物をスクリー二 ングするためのキットであって、 指標遺伝子が請求項 1における a)〜 、 並 ぴに c' )および d' )のいずれかに記載の群から選択されたいずれかの遺伝子で ある ツト。  17. A kit for screening a therapeutic compound for the treatment of atopic dermatitis, comprising an antibody that recognizes a protein encoded by an indicator gene and a cell that expresses the indicator gene, wherein the indicator gene is used. 2. A gene selected from the group described in any one of a) to c) and d ') according to claim 1.
1 8 . 指標遺伝子または指標遺伝子と機能的に同等な遺伝子の皮膚における発 現強度を上昇させたトランスジヱニック非ヒト脊椎動物からなるアトピー性 皮膚炎モデル動物であって、 指標遺伝子が請求項 1における a)、 c)、 および c' )、 並びに以下の A)または C)に記載の群から選択されたいずれかの遺伝子 であるモデル動物。  1 8. An atopic dermatitis model animal comprising a transgenic non-human vertebrate with an increased expression intensity in the skin of an indicator gene or a gene functionally equivalent to the indicator gene, wherein the indicator gene is claimed. A) a model animal which is a gene selected from a), c), and c ′) in 1 and any one of the groups described in A) or C) below.
A)以下の遺伝子からなる、 ダニァレルゲン感作マゥスの耳介皮膚における発 現レベルがダニアレルゲン非感作マウスの耳介皮膚に比べて高い指標遺伝子 群： Cathepsin C、 Matrix metalloproteinase 9、 Granzyme B、 M. mus cuius 24p 3 gene、 Interleukin 7 receptor N Interleukin 6、 interleukin 4 receptor, alpha^ Mus musculus cDNA /clone=2900006G01、 Interleukin 3 receptor, bet a chain 1、 Small inducible cytokine A2、 Macrophage inflammatory proteinA) An indicator gene group consisting of the following genes, whose expression level in the auricle skin of mite allergen-sensitized mice is higher than that of the mite allergen-unsensitized mice: Cathepsin C, Matrix metalloproteinase 9, Granzyme B, M mus cuius 24p 3 gene, Interleukin 7 receptor N Interleukin 6, interleukin 4 receptor, alpha ^ Mus musculus cDNA / clone = 2900006G01, Interleukin 3 receptor, bet a chain 1, Small inducible cytokine A2, Macrophage inflammatory protein
2、 monocyte cheraoattractant protein-2 (MCP-2) precursor N Chemokine (C- C) receptor 1、 intracellular calcium-binding protein (MRP8)、 intracellu lar ca丄 cium- binding protein (MRP 14) N complement receptor 3 beta subunit2, monocyte cheraoattractant protein-2 (MCP-2) precursor N Chemokine (C-C) receptor 1, intracellular calcium-binding protein (MRP8), intracellu lar ca 丄 cium-binding protein (MRP 14) N complement receptor 3 beta subunit
MAC - 1、 upl4b05. xl、 rumor necrosis factor induced protein 6、 cell surfa ce glycoprotein CD53、 Mus musculus cDNA, 3 end /clone=4732410E23 Tenas cin C、 Mouse proteoglycan core proteinN Mouse beta Fc receptor type II (FCRII)、 Hemopoietic cell kinase^ Mouse mRNA for protein tyrosine phosp hatase epsilor ma72f04. xl、 keratin 16、 Small proline— rich protein 2A、 SPRRlb protein^ Mus musculus cDNA /clone=2210020E15 Signal transducer and activator of transcription 1、 Mus musculus cDNA, 3 end /clone=73304 23G02、 およぴ TYRO protein tyrosine kinase binding protein MAC-1, upl4b05.xl, rumor necrosis factor induced protein 6, cell surfa ce glycoprotein CD53, Mus musculus cDNA, 3 end / clone = 4732410E23 Tenas cin C, Mouse proteoglycan core protein N Mouse beta Fc receptor type II (FCRII), Hemopoietic cell kinase ^ Mouse mRNA for protein tyrosine phosp hatase epsilor ma72f04.xl, keratin 16, Small proline- rich protein 2A, SPRRlb protein ^ Mus musculus cDNA / clone = 2210020E15 Signal transducer and activator of transcription 1, Mus musculus cDNA, 3 end / clone = 73304 23G02, and TYRO protein tyrosine kinase binding protein
C)以下の遺伝子からなる、 DNFB反復塗布接触性皮膚炎モデルマウスの耳介皮 膚における発現レベルが DNFB反復塗布前のマウスの耳介皮膚に比べて高い指標 JIMK子群： matrix metalloproteinase 12、 cathepsin Z、 Granzyme B、 proteas e, serine, 18、 lipocalin 2、 tissue inhibitor of metalloproteinase 1、 in terleukin 4 receptor, alphas pre— B - cell colony - enhancing factor epari n binding epidermal growth factor-like growth fact or % colony stimulatin g factor 2 receptor, beta 1， low- affinity (granulocyte— macrophage)、 chem okine (C- C motif) ligand 3、 MCP - 1、 Macrophage inflammatory protein 2、 C hemokine (C - C) receptor 1、 chemokine (C - X - C motif) ligand 11、 intracell ular calcium- binding protein (MRP8)、 intracellular calcium - binding prot ein (MRP14) CD 163 antigenN CD53、 Lyn、 cholesterol 25- ydroxylaseN phos pholipid scramblase 1、 superoxide dismutase 2, mitochondrial keratin c omplex 2, basic, gene 6as keratin 16、 small proline— rich protein 1B、 In terferon- stimulated protei 15、 RIKEN cDNA 1700093E07 gene, nel— like 2 homo log (chicken)、 lysosomal— associated protein transmembrane 5、 fibrob last growth factor binding protein 1、 および fibrinogen— like protein 2 1 9 . 非ヒト脊椎動物がマウスである請求項 1 8に記載のモデル動物。 C) Higher expression level in the auricle skin of DNFB-repeat-applied contact dermatitis model mice compared to auricle skin of mice before DNFB-repeat application, consisting of the following genes: JIMK children: matrix metalloproteinase 12, cathepsin Z, Granzyme B, proteas e, serine, 18, lipocalin 2, tissue inhibitor of metalloproteinase 1, in terleukin 4 receptor, alpha s pre-- B-cell colony-enhancing factor epari n binding epidermal growth factor-like growth fact or % colony stimulatin g factor 2 receptor, beta 1, low-affinity (granulocyte- macrophage), chemokine (C-C motif) ligand 3, MCP-1, Macrophage inflammatory protein 2, C hemokine (C-C) receptor 1, chemokine ( C-X-C motif) ligand 11, intracellular calcium-binding protein (MRP8), intracellular calcium-binding protein (MRP14) CD 163 antigen N CD53, Lyn, cholesterol 25-ydroxylase N phos pholipid scramblase 1, superoxide dismutase 2 , mitochondrial keratin c omplex 2, basic, gene 6a s keratin 16, small proline- rich protein 1B, Interferon- stimulated protei 15, RIKEN cDNA 1700093E07 gene, nel- like 2 homo log (chicken), lysosomal- associated protein transmembrane 5, fibrob last growth factor binding protein 1, and fibrinogen-like protein 2 19. The model animal according to claim 18, wherein the non-human vertebrate is a mouse.
2 0 . 指標遺伝子または指標遺伝子と機能的に同等な遺伝子の皮膚における発 現強度を低下させたトランスジヱニック非ヒト脊椎動物からなるアトピー性 皮膚炎モデル動物であって、 指標遺伝子が請求項 1における b)、 d)、 および d' )、 並びに以下の B)または D)に記載の群から選択されたいずれかの遺伝子 であるモデル動物。  20. An atopic dermatitis model animal comprising a transgenic non-human vertebrate with reduced expression intensity in the skin of an indicator gene or a gene functionally equivalent to the indicator gene, wherein the indicator gene is a claim. A model animal which is b), d) and d ') in 1 and any one of the genes selected from the group described in B) or D) below.
B) 以下の遺伝子からなる、 ダニアレルゲン感作マウスの耳介皮膚における発 現レベルがダニアレルゲン非感作マウスの耳介皮膚に比べて低い指標遺伝子 群： MEP mRNA、 sciellin Putative OrthologN Id4 dominant negative helix - 1 oop-helix gene、 metallothionein 4 Putative 0rtholog、 retinol binding pr otein (RBP)、 および RIKEN cDNA 0610006G05 gene B) An indicator gene consisting of the following genes, whose expression level in the auricle skin of mite-allergen-sensitized mice is lower than that in the ear skin of mite-allergen-unsensitized mice Groups: MEP mRNA, sciellin Putative Ortholog N Id4 dominant negative helix-1 oop-helix gene, metallothionein 4 Putative 0rtholog, retinol binding protein (RBP), and RIKEN cDNA 0610006G05 gene
D) 以下の遺伝子からなる、 DNFB反復塗布接触性皮膚炎モデルマゥスの耳介皮 膚における発現レベルが DNFB反復塗布前のマウスの耳介皮膚に比べて低い指標 遺 子群： keratin comple 1, acidic, gene 15、 sciellin Putative Ortholo g、 protein tyrosine phosphatase, non-receptor type 21、 expressed sequen ce AM94241、 apolipoprotein D、 GATA binding protein 3、 Id4 dominant neg ative helix-loop-helix gene, RIKEN cDNA 4631434019 gene, CDCREL-1 homol og、 adipocyte complement related protein of 30 kDa、 丄 oricrin、 cDNA, 5' end  D) An index consisting of the following genes, whose expression level in the auricle skin of the DNFB repetitively applied contact dermatitis model mouse is lower than that of the mouse auricle skin before the repeated application of DNFB. Gene groups: keratin comple 1, acidic, gene 15, sciellin Putative Ortholog, protein tyrosine phosphatase, non-receptor type 21, expressed sequence AM94241, apolipoprotein D, GATA binding protein 3, Id4 dominant negative helix-loop-helix gene, RIKEN cDNA 4631434019 gene, CDCREL-1 homolog, adipocyte complement related protein of 30 kDa, 丄 oricrin, cDNA, 5 'end
2 1 . 非ヒト脊椎動物がマウスである請求項 2 0に記載のモデル動物。  21. The model animal according to claim 20, wherein the non-human vertebrate is a mouse.
2 2 . 次の i) -iv)のいずれかに記載の成分をマウスに投与する工程を含む、 ァ レルギ一性皮膚炎モデル動物め製造方法。  22. A method for producing an animal model for allergic allergic dermatitis, comprising a step of administering the ingredient described in any of the following i) to iv) to a mouse.
i)請求項 1 8における A)および C)に記載の遺伝子群から選択されたいずれ 力の遺伝子を構成する塩基配列を含むポリヌクレオチド、  i) a polynucleotide comprising a nucleotide sequence constituting any of the genes selected from the group of genes according to A) and C) according to claim 18;
ii)請求項 1 8における A)および C)に記載の遺伝子群から選択されたいずれ 力 >の遺伝子を構成する塩基配列を含むポリヌクレオチドによってコードさ れるタンパク質  ii) a protein encoded by a polynucleotide comprising a nucleotide sequence that constitutes a gene selected from the group of genes according to A) and C) according to claim 18;
iii)請求項 2 0における B)および D)に記載の遺伝子群から選択されたいず れかの遺伝子を構成する塩基配列を含むポリヌクレオチドのアンチセンスま たは R i  iii) Antisense or R i of a polynucleotide comprising a nucleotide sequence constituting any of the genes selected from the group of genes according to B) and D) in claim 20
iv)請求項 2 0における B)および D)に記載の遺伝子群から選択されたいずれ かの遺伝子を構成する塩基配列を含むポリヌクレオチドによってコードさ れるタンパク質に結合する抗体、 またはその抗原結合領域を含む断片 iv) an antibody that binds to a protein encoded by a polynucleotide containing a nucleotide sequence comprising any of the genes selected from the group of genes according to claim 20), or an antigen-binding region thereof. Fragment containing
2 3 . 請求項 2 2における i) - iv)のいずれかに記載の成分を有効成分として含 3 6 & ：; 23. The composition according to any one of claims 22 to i) to iv) as an active ingredient. 3 6 &:;
む、 マウスにアレルギー性皮膚炎を誘導するための誘導剤。 An inducer for inducing allergic dermatitis in mice.
4 . 次の工程を含む、 アトピー性皮膚炎の治療薬のスクリーニング方法であ つて、 指標遺伝子が請求項 1における a)〜d)、 請求項 1における c' )および d Ί , 請求項 1 8における A)および C)、 および請求項 2 0における B)および D)のいずれかに記載の群から選択されたいずれかの遺伝子、 または指標遺伝 子と機能的に同等な遺伝子であるスクリーニング方法。 4. A method for screening for a therapeutic agent for atopic dermatitis, comprising the following steps, wherein the indicator genes are a) to d) in claim 1, c ′) and d に お け る in claim 1, and claim 18. 20. A screening method which is a gene selected from the group according to any one of A) and C) in claim 20 and B) and D) in claim 20, or a gene functionally equivalent to the indicator gene.
( 1 ) 被験動物に候補化合物を投与する工程、  (1) administering a candidate compound to a test animal,
( 2 ) 前記被験動物の生体試料における指標遺伝子の発現強度を測定する工程、 (2) measuring the expression intensity of the indicator gene in the biological sample of the test animal,
( 3 ) 候補化合物を接触させない対照と比較して、 a)群、 c)群、 c' )群、 A)群、 並びに C)群の指標遺伝子については前記遺伝子の発現レベルを低下させる 化合物を、 また b)群、 d)群、 d' )群、 B)群、 並びに D)群の指標遺伝子につい ては前記遺伝子の発現レベルを上昇させる化合物を選択する工程、 (3) Compared to a control not contacted with a candidate compound, a compound that reduces the expression level of the marker gene of the a) group, c) group, c ′) group, A) group, and C) group is used. And selecting a compound that increases the expression level of the indicator gene of the group b), the group d), the group d '), the group B), and the group D),
5 . 次の工程を含む、 アトピー性皮膚炎の治療薬のスクリーニング方法であ つて、 指標遺伝子が請求項 1における a)〜d)、 並びに c' )および d' )のいずれ かに記載の群から選択されたいずれかの遺伝子、 または指標遺伝子と機能的 に同等な遺伝子であるスクリーニング方法。  5. A method for screening a therapeutic agent for atopic dermatitis, comprising the following steps, wherein the indicator gene is the group according to any one of claims 1) to d), and any of c ′) and d ′) A screening method which is a gene selected from the group consisting of: or a gene functionally equivalent to an indicator gene.
( 1 ) 指標遺伝子の転写調節領域と、 この転写調節領域の制御下に発現するレ ポータ一遺伝子とを含むベクタ一を導入した細胞と候補化合物を接触させる 工程、  (1) contacting a candidate compound with a cell into which a vector containing a transcription regulatory region of an indicator gene and a reporter gene expressed under the control of the transcription regulatory region has been introduced;
( 2 ) 前記レポーター遺伝子の活性を測定する工程、 および  (2) measuring the activity of the reporter gene, and
( 3 ) 候補ィ匕合物を接触させない対照と比較して、 a)群、 c)群、 および ）群 のいずれかの指標遺伝子についてほ前記レポーター遺伝子の発現レベルを低 下させる化合物を、 また b)群、 d)群、 および d' )群のいずれかの指標遺伝子 については前記レポーター遺伝子の発現レベルを上昇させる化合物を選択す る工程、  (3) a compound that reduces the expression level of the reporter gene for any of the indicator genes of a) group, c) group, and selecting a compound that increases the expression level of the reporter gene for any of the indicator genes of groups b), d) and d ′);
6 . 次の工程を含む、 アトピー性皮膚炎の治療薬のスクリーニング方法であ つて、 指標遺伝子が請求項 1における a)〜 、 並びに c' )および d' )のいずれ かに記載の群から選択されたいずれかの遺伝子、 または指標遺伝子と機能的 に同等な遺伝子であるスクリーニング方法。 6. A method for screening for a therapeutic agent for atopic dermatitis, comprising the following steps: Screening wherein the indicator gene is a gene selected from the group of a) to, and c ′) and d ′) in claim 1, or a gene functionally equivalent to the indicator gene. Method.
( 1 ) 指標遺伝子によってコードされる蛋白質と候補化合物を接触させる工程、 (1) contacting a protein encoded by the indicator gene with a candidate compound,
( 2 ) 前記蛋白質の活性を測定する工程、 および (2) measuring the activity of the protein, and
( 3 ) 候補ィ匕合物を接触させない対照と比較して、 a)群、 c)群、 および c' )群 のいずれかの指標遺伝子については前記活性を低下させる化合物を、 また b)群、 d)群、 および d' )群のいずれかの指標遺伝子については前記活性を上 昇させる化合物を選択する工程  (3) a compound that decreases the activity for any of the index genes of the a) group, c) group, and c ′) group, Selecting a compound that increases the activity for any of the indicator genes of groups d), d) and d ')
7 . 請求項 1 4、 請求項 2 4、 請求項 2 5、 および請求項 2 6のいずれかに 記載のスクリーニング方法によって得ることができる化合物を有効成分とし て含有する、 アトピ一性皮膚炎の治療薬。 7. Atopic dermatitis comprising a compound obtainable by the screening method according to any one of claims 14, 24, 25, and 26 as an active ingredient. Therapeutic drugs.
8 . 指標遺伝子、 またはその一部のアンチセンス DNA を有効成分として含む アトピー性皮膚炎の治療薬であって、 指標遺伝子が請求項 1における a)、 c) , および c' )のいずれかに記載の群から選択されたいずれかの遺伝子である治療 9 . 指標遺伝子によってコードされる蛋白質を認識する抗体を有効成分とし て含む、 アトピー性皮膚炎の治療薬であって、 指標遺伝子が請求項 1におけ る a)、 c) s および c，）のいずれかに記載の群から選択されたいずれかの遺伝 子である治療薬。 8. A therapeutic agent for atopic dermatitis containing an indicator gene or a part thereof antisense DNA as an active ingredient, wherein the indicator gene is any one of a), c), and c ') in claim 1. 9. A therapeutic agent for atopic dermatitis, comprising as an active ingredient an antibody that recognizes a protein encoded by an indicator gene, wherein the indicator gene is any one of the genes selected from the group described in claim 9. A), c) a therapeutic agent which is any one of the genes selected from the group described in any of s and c,).
0 . 指標遺伝子、 または指標遺伝子によってコードされる蛋白質を有効成分 として含む、 アトピー性皮膚炎の治療薬であって、 指標遺伝子が請求項 1に おける b；)、 d)、 および d' )のいずれかに記載の群から選択されたいずれかの 遺伝子である治療薬。  0. A therapeutic agent for atopic dermatitis, which comprises, as an active ingredient, an indicator gene or a protein encoded by the indicator gene, wherein the indicator gene is selected from b;), d) and d ') according to claim 1 A therapeutic agent which is any gene selected from the group described in any of the above.
1 . 指標遺伝子を測定するためのプローブを固定したアトピー性皮膚炎の診 断用 DNAチップであって、 指標遺伝子が請求項 1に記載された a)群〜 d)群、 並びに c' )および d' )のいずれかから選択された少なくとも 1種類の遺伝子で ある DNAチップ。 1. A DNA chip for diagnosing atopic dermatitis on which a probe for measuring an indicator gene is fixed, wherein the indicator gene is a group to a) group to d) group according to claim 1. And a DNA chip which is at least one gene selected from any of c ′) and d ′).
3 2 . 次の工程 ( 1 ) 〜 （3 ) を含む、 乾癬の検査方法であって、 指標遺伝子 が次の i)〜iv)の'いずれかに記載の群から選択されたいずれかの遺伝子である 方法。  32. A psoriasis test method comprising the following steps (1) to (3), wherein the indicator gene is any one of the following groups i) to iv): Is the way.
( 1 ) 被検者の皮疹部および/または無疹部から採取された生体試料における 指標遺伝子の発現レベルを測定する工程  (1) A step of measuring the expression level of an indicator gene in a biological sample collected from a skin eruption and / or a rash of a subject
( 2 ) 工程 ( 1 ) で測定された発現レベルを、 指標遺伝子が i)または ii)に記 载された遺伝子である場合には、 対照として同じ被検者の無疹部から採取さ. れた生体試料における指標遺伝子の発現レベルと、 また指標遺伝子が iii) または iv)に記載された遺伝子である場合には、 対照として健常者の生体試 料における指標遺伝子の発現レベルと比較する工程、 および  (2) The expression level measured in step (1) is collected from the rash-free area of the same subject as a control when the indicator gene is the gene described in i) or ii). Comparing the expression level of the indicator gene in the biological sample obtained and the expression level of the indicator gene in a biological sample of a healthy subject as a control, if the indicator gene is a gene described in iii) or iv), and
( 3 ) ( 2 ) の比較の結果、 指標遺伝子が i)または iii)に記載された遺伝子の 場合には対照と比較して発現レベルが高い場合に、 また指標遺伝子が ii)ま たは iv)に記載された遺伝子の場合には対照と比較して発現レベルが低い場 合に、 前記被検者は乾癬を有すると判定する工程  (3) As a result of the comparison in (2), when the indicator gene is the gene described in i) or iii), the expression level is higher than the control, and when the indicator gene is ii) or iv. A) determining that the subject has psoriasis when the expression level of the gene described in
i) 以下の遺伝子からなる、 乾癬の患者において皮疹部における発現レベルが 無疹咅 βに比べて高い指標遺伝子群： cellular retinoic acid binding protein 2、 proteasome (prosome, macropain) activator subunit 2、 interferon indu ced 6 - 16 protein^ heat shock 70kDa protein 4、 flap structure-specific e ndonuclease 1、 NME1、 cycl in— dependent kinase inhibitor 3、 ubi qui tin-con jugating enzyme E2C、 calreticulin、 CDC2 gene、 RAN、 liver arginase (ARG 1.)、 connexin 43 (GJAl, Cx43)、 interleukin 1 receptor antagonist^ ATP - bi nding cassette, sub-family A (ABCl) , member 12、 M- phase phosphoprotein 6、 creatine kinase, mitochondrial 1、 edd4 binding protein 1、 solute ca rrier family 7, member 5、 acid phosphatase, prostate^ plakophilin 1、 UD P glycosyltransf erase 1 family, polypeptide A4、 ATPase, H+/K+ transport ing, nongastric, alpha polypeptide^ cytoskeleton - associated protein 4、 g丄 ucosidase, beta; acid、 interferon-inducible 56 Kd protein^ low dens it y lipoprotein receptor s transglutaminase 3、 arachidonate 12-lipoxygenas e, 12R type、 CYP7B1、 tripartite motif-containing 14、 hypothetical prote in FLJ21168、 heme oxygenase (decycling) 1、 SIOO calcium binding proteini) Indicator genes consisting of the following genes, whose expression levels in the rash area are higher than those in the rash in psoriatic patients compared to rash β: cellular retinoic acid binding protein 2, proteasome (prosome, macropain) activator subunit 2, interferon induced 6-16 protein ^ heat shock 70kDa protein 4, flap structure-specific edonuclease 1, NME1, cycl in- dependent kinase inhibitor 3, ubi qui tin-con jugating enzyme E2C, calreticulin, CDC2 gene, RAN, liver arginase (ARG 1 .), Connexin 43 (GJAl, Cx43), interleukin 1 receptor antagonist ^ ATP-binding cassette, sub-family A (ABCl), member 12, M-phase phosphoprotein 6, creatine kinase, mitochondrial 1, edd4 binding protein 1, solute carrier family 7, member 5, acid phosphatase, prostate ^ plakophilin 1, UD P glycosyltransf erase 1 family, polypeptide A4, ATPase, H + / K + transporting, nongastric, alpha polypeptide ^ cytoskeleton-associated protein 4, g 丄 ucosidase, beta; acid, interferon-inducible 56 Kd protein ^ low dens it y lipoprotein receptor s transglutaminase 3, arachidonate 12-lipoxygenas e, 12R type, CYP7B1, tripartite motif-containing 14, hypothetical prote in FLJ21168, heme oxygenase (decycling) 1, SIOO calcium binding protein
P、 gene from PAC 747L4N SAM domain and HD domain 1、 arylsulfatase F、 p otassium inwardly-rectifying channel, subfamily J, member 15、 BUBl budd ing uninhibited by benz imidazoles 1 omolog beta (yeast) SPllO nuclear body protein isoform b、 guanylate binding protein 1 (GBP1)、 GM2 gangli oside activator prote in complement factor B preproprotein,, squalene ep oxidase^ solute carrier family 5 (sodium/glucose cotransporter) , memberP, gene from PAC 747L4 N SAM domain and HD domain 1, arylsulfatase F, pototium inwardly-rectifying channel, subfamily J, member 15, BUBl budding uninhibited by benz imidazoles 1 omolog beta (yeast) SPllO nuclear body protein isoform b, guanylate binding protein 1 (GBP1), GM2 gangli oside activator prote in complement factor B preproprotein ,, squalene ep oxidase ^ solute carrier family 5 (sodium / glucose cotransporter), member
1、 ZW10 interactor Zwint、 kallikrein 13、 interferon regulatory factor 7、 N-myc (and STAT) interactor Stat2、 tripartite motif- containing 22、 kinesin - like 6、 kallikrein 10、 ribonucleotide reductase M2 polypeptide^ chromosome 1 open reading frame 29、 Sjogren syndrome antigen ΛΐΝ gamma— glutamyl hydrolase^ lymphocyte antigen 6 complex, locus E、 interleukm- 1 receptor antagonist^ interferon— induced protein 44、 lectin, galactosi de-binding, soluble, 3 binding protein^ retinoblastoma binding protein 6、 vipirin、 interferon-induced protein with tetratricopeptide repeats 4、 SIOO calcium binding protein A12 (calgranulin C)、 bone marrow stromal c ell antigen 2、 chromosome 20 open reading frame 1、 aquaporin 3、 cystati n A (stef in A)、 KIAA0186、 ； retinoblastoma - associated protein HEC、 NS1- as sociated protein 1、 topoisomerase (DNA) II alpha 170kDa、 H2A histone fa mily, member X、 chemokine exodus- 1、 pituitary tumor-transforming 1、 SCO cytochrome oxidase deficient homolog 2 (yeast) N CDC28 protein kinase r egulatory subunit 2、 kinesin - like 1、 histidine ammonia -丄 yase、 hypotheti cal protein FLJ"10534、 cyclin El、 chromosome 1 open reading frame 34、 ce llular retinoic acid binding protein 2、 TTK protein kinase^ acid phosph atase, prostate、 interleukin 8 receptor beta (Iし 8RB)、 讓 27A、 MX2、 thym idine kinase 1、 interferon- inducible 56 Kd protein^ serum/glucocort i coi d regulated kinase^ EphA2、 nitric oxide synthase 2A、 plasminogen activa tor, tissue type、 GM2 ganglioside activator proteinN KIAA0963 protein^ kallikrein 13、 ATPase, Class V， type 10B、 GART、 cathepsin C、 airway try psin— like protease^ serine protease— like protein^ protease M、 trypsinog en IV b— form、 neutrophil gelatinase associated lipocalin、 squamous cell carcinoma antigen=serine protease inhibitor squamous cell carcinoma a ntigen 2 (SCCA2)、 mononcyte/neutrophi 1 elastase inhibitor^ alpha 1-anti trypsin^ elaf ίη interleukin— 7 receptor interleukin 4 receptor N platel et— derived endothelial cell growth factor ^ pre-B cell enhancing factor (PBEF)、 alternative activated macrophage specific CC chemokine 1、 lacto transferrin^ melanoma growth stimulatory activity (MGSA) I Gro a丄 pha、 p soriasin (S100A7)、 MRP - 8 (S100A8)、 MRP— M (S100A9)、 CaN19 (S100A2)、 p cad herin、 130-kD pemphigus vulgaris antigen I Desmoglein 3、 desmocollins t ype 2b、 CD24 signal transducer、 0A3 antigenic surface determinant / CD4 7、 monocyte/macrophage Ig- related receptor MIR— 7 / CD85、 lyn、 protein t yrosine phosphatase, receptor type, E isoforml，2、 tartrate— resistant ac id phosphatase type 5、 cholesterol 25- hydroxylase、 Phospholipid scrambl ase 1、 manganese superoxide dismutase (EC 1. 15. 1. 1)、 uridine phosphoryl ase、 aldose reductase-丄 ike peptide^ 2'， 5， oligoadenylate synthetase iso form E16, E18、 2， , 5' oligoadenylate synthetase 2 isoform p69， p71、 L-ky nurenine hydrolase、 purine nucleoside phosphorylase (PNP ; EC 2, 4. 2. 1)、 3 7 1 ：: ' ' ； 1, ZW10 interactor Zwint, kallikrein 13, interferon regulatory factor 7, N-myc (and STAT) interactor Stat2, tripartite motif-containing 22, kinesin-like 6, kallikrein 10, ribonucleotide reductase M2 polypeptide ^ chromosome 1 open reading frame 29, Sjogren syndrome antigen Λΐ Ν gamma- glutamyl hydrolase ^ lymphocyte antigen 6 complex, locus E, interleukm-1 receptor antagonist ^ interferon- induced protein 44, lectin, galactosi de-binding, soluble, 3 binding protein ^ retinoblastoma binding protein 6, vipirin, interferon-induced protein with tetratricopeptide repeats 4, SIOO calcium binding protein A12 (calgranulin C), bone marrow stromal cell antigen 2, chromosome 20 open reading frame 1, aquaporin 3, cystatin A (stef in A), KIAA0186, retinoblastoma -associated protein HEC, NS1-as sociated protein 1, topoisomerase (DNA) II alpha 170kDa, H2A histone fa mily, member X, chemokine exodus-1, pituitary tumor-transforming 1, SCO cytochrome oxidase deficient homolog 2 (yeast) N CDC28 protein kinase r egulatory subunit 2, kinesin-like 1, histidine ammonia- 丄 yase, hypotheti cal protein FLJ "10534, cyclin El, chromosome 1 open reading frame 34, ce llular retinoic acid binding protein 2, TTK protein kinase ^ acid phosph atase, prostate, interleukin 8 receptor beta (I and 8RB), acetyl 27A, MX2, thymidine kinase 1, interferon-inducible 56 Kd protein ^ serum / glucocorticoid regulated kinase ^ EphA2, nitric oxide synthase 2A, plasminogen activa tor, tissue type, GM2 ganglioside activator protein N KIAA0963 protein ^ kallikrein 13, ATPase, Class V, type 10B, GART, cathepsin C, airway try psin— like protease ^ serine protease— like protein ^ protease M, trypsinog en IV b—form, neutrophil gelatinase associated lipocalin, squamous cell carcinoma antigen = serine protease inhibitor squamous cell carcinoma a ntigen 2 (SCCA2), mononcyte / neutrophi 1 elastase inhibitor ^ alpha 1-anti trypsin ^ elaf ίη interleukin— 7 receptor interleukin 4 recepto r N platel et- derived endothelial cell growth factor ^ pre-B cell enhancing factor (PBEF), alternative activated macrophage specific CC chemokine 1, lacto transferrin ^ melanoma growth stimulatory activity (MGSA) I Gro a 丄 pha, p soriasin (S100A7) , MRP-8 (S100A8), MRP-M (S100A9), CaN19 (S100A2), p cad herin, 130-kD pemphigus vulgaris antigen I Desmoglein 3, desmocollins type 2b, CD24 signal transducer, 0A3 antigenic surface determinant / CD47 , Monocyte / macrophage Ig-related receptor MIR—7 / CD85, lyn, protein tyrosine phosphatase, receptor type, E isoforml, 2, tartrate—resistant ac id phosphatase type 5, cholesterol 25-hydroxylase, Phospholipid scramblase 1, manganese superoxide dismutase (EC 1.15.1.1), uridine phosphorylase, aldose reductase- 丄 ike peptide ^ 2 ', 5, oligoadenylate synthetase iso form E16, E18, 2,, 5' oligoadenylate synthetase 2 isoform p69, p71, L -ky nurenine hydrolase, purine nucleoside ph osphorylase (PNP; EC 2, 4.2.1), 3 7 1 :: '';
2'， 5， oligoadenylate synthetase - like (59 kDa isoform)、 cytokeratin 17、 keratin 6A、 keratin 16、 myosin VA (heavy polypeptide 12, myoxin〉、 Small proline-rich protein SPRK、 small proline-rich protein 2A、 small prolin e - rich protein IB (cornifin)、 involucrin^ interferon-inducible protein p78 (MX1)、 interferon-induced 17 - kDa/15-kDa protein^ p27, interferon - al pha - inducible protein 27、 regulator of G- protein signalling 20、 STATU cyclin B、 proto - oncogene (Wnt-5a) beta defensin 2 (HBD2)、 KIM0101、 tu mor suppressing sub transferable candidate 3 (TSSC3)、 heparin binding pr otein (HBpl7) / FGF— BP1、 およぴ transcobalamin I  2 ', 5, oligoadenylate synthetase-like (59 kDa isoform), cytokeratin 17, keratin 6A, keratin 16, myosin VA (heavy polypeptide 12, myoxin>, Small proline-rich protein SPRK, small proline-rich protein 2A, small prolin e-rich protein IB (cornifin), involucrin ^ interferon-inducible protein p78 (MX1), interferon-induced 17-kDa / 15-kDa protein ^ p27, interferon-al pha-inducible protein 27, regulator of G- protein signaling 20 , STATU cyclin B, proto-oncogene (Wnt-5a) beta defensin 2 (HBD2), KIM0101, tu mor suppressing sub transferable candidate 3 (TSSC3), heparin binding pr otein (HBpl7) / FGF-BP1, and transcobalamin I
ii) 以下の遺伝子からなる、 乾癬の患者において皮疹部における発現レベル が無疹部に比べて低い指標遺伝子群： actin, alpha 2, smooth muscle, aorta, actin, gamma 2， smooth muscle, enteric^, cisplatin resistance associated,, growth arrest-specific 6、 insulin-like growth factor binding protein 6 (IGFBP6) insulin induced protein 1 (INSIG1)、 PDGF receptor beta-like t uraor suppressor (PRLTS) N R - rasゝ sarcospan (Kras oncogene— associated gen e)、 fibroblast growth factor (FGF) receptor - 1、 f ibronectin 1 isoform 1 preproprotein^ chromosome 21 open reading frame 25、 seven in absentia h omolog 1 (Drosophila)、 fatty acid desaturase 1、 fatty acid desaturase 2、 Rho- related BTB domain containing 3、 matrilin 2、 adipose specific 2、 LI M protein LIM domain binding 2 / CLIM1、 myosin light chain kinase (MLC K)、 myosin, light polypeptide 9, regulatoryゝ tropomyosin 1 (alpha) N cys teine- rich protein 1 (intestinal) N reversion- inducing- cysteine- ricn pro tein with kazal motifs^ amine oxidase, copper containing 3 (vascular ad hesion protein 1)、 cytochrome c oxidase subunit Vila polypeptide 1 (mus cle)、 chemokine (C_C motif) ligand 14、 ocular deve丄 opment - associated ge ne、 ephrin- B2、 Na, K-ATPase subunit alpha 2 (ATP1A2) , ATPase, Ca++ trans 3 7 ¾ 二，— ii) An indicator group consisting of the following genes, whose expression level in the rash area is lower in psoriatic patients than in the rash area: actin, alpha 2, smooth muscle, aorta, actin, gamma 2, smooth muscle, enteric ^, cisplatin resistance associated ,, growth arrest-specific 6, insulin-like growth factor binding protein 6 (IGFBP6) insulin induced protein 1 (INSIG1), PDGF receptor beta-like t uraor suppressor (PRLTS) N R-ras ゝ sarcospan (Kras oncogene — Associated gene e), fibroblast growth factor (FGF) receptor-1, fibronectin 1 isoform 1 preproprotein ^ chromosome 21 open reading frame 25, seven in absentia homolog 1 (Drosophila), fatty acid desaturase 1, fatty acid desaturase 2, Rho-related BTB domain containing 3, matrilin 2, adipose specific 2, LI M protein LIM domain binding 2 / CLIM1, myosin light chain kinase (MLC K), myosin, light polypeptide 9, regulatory tropomyosin 1 (alpha) N cys teine -rich protein 1 (intestinal) N reversi on- inducing- cysteine- ricn pro tein with kazal motifs ^ amine oxidase, copper containing 3 (vascular ad hesion protein 1), cytochrome c oxidase subunit Vila polypeptide 1 (mus cle), chemokine (C_C motif) ligand 14, ocular deve 丄opment-associated gene, ephrin-B2, Na, K-ATPase subunit alpha 2 (ATP1A2), ATPase, Ca ++ trans 3 7 ¾ two,
porting, ubiquitous^ aquaporin 9、 pleiotrophin^ cadherin 19, type 2、 丽 T inhibitory factor 1、 WNTl inducible signaling pathway protein 2、 11-b eta-hydr oxy st ero i d dehydrogenase (HSD11)、 myelin basic protein (MBP)ヽ p ro - galanin、 dihydropyr imidinase-1 ike 3、 glypican-4 (GPC4)、 acetylseroto nin 0— methyl transferase - like、 synuclein, ga讓 a、 connective tissue growt h factor s breast cancer anti-estrogen resistance 3、 heat shock 70kDa pr otein 2、 ets variant gene 1、 cAMP - dependent protein kinase subunit RII - beta、 microtubule - associated protein, RP/EB family, member 2、 ATP-bindi ng cassette, sub-family C (CFTR/MRP) , member 3ゝ transmembrane 4 superfa mi丄 y member 2、 AXL receptor tyrosine kinase、 phospholamban^ Fc fragment of IgG binding protein^ microsomal glutathione S - transferase 3、 DEPP (decidual protein induced by progesterone)、 Arg/Abl- interacting proteinporting, ubiquitous ^ aquaporin 9, pleiotrophin ^ cadherin 19, type 2, 丽 T inhibitory factor 1, WNTl inducible signaling pathway protein 2, 11-beta-hydroxy stero id dehydrogenase (HSD11), myelin basic protein (MBP) ヽpro-galanin, dihydropyr imidinase-1 ike 3, glypican-4 (GPC4), acetylseroto nin 0- methyl transferase-like, synuclein, ga les a, connective tissue growt h factor s breast cancer anti-estrogen resistance 3, heat shock 70kDa protein 2, ets variant gene 1, cAMP-dependent protein kinase subunit RII-beta, microtubule-associated protein, RP / EB family, member 2, ATP-bindin cassette, sub-family C (CFTR / MRP), member 3 ゝ transmembrane 4 superfa mi 丄 y member 2, AXL receptor tyrosine kinase, phospholamban ^ Fc fragment of IgG binding protein ^ microsomal glutathione S-transferase 3, DEPP (decidual protein induced by progesterone), Arg / Abl- interacting protein
ArgBP2a (ArgBP2a) s H0X2H mRNA from the Hox2 locus、 frizzled- related pr otein、 G protein-coupled receptor, family C, group 5, member B、 GABA-A receptor pi subunit^ mesenchyme homeo box 2 (growth arrest-specific hom eo box)、 keratin 7、 tumor-associated calcium signal transducer 1、 dioxi n - inducible cytochrome P450 (CYP1B1)、 interleukin 1 receptor, type II、 platelet/endothelial cell adhesion molecule (CD31antigen) N GRB2-associa ted binding protein 2、 mitogen inducible 2、 ransgelin、 deleted in live T cancer 1、 8-oxoguanine DNA g丄 ycosylase、 enolase 2, (gamma, neuronal) 、 pinin, desmosome associated protein^ KIAA0367 gene、 KIAA0280 gene、 KIAA 1053 proteins KIAA0729 protein, KIAA1467 protein, KIAA0716 protein, hyp othetical gene CG018、 hypothetical protein FLJ13612、 FLJ90798, DKFZp586 11823、 D FZp5640222s kallikreinl, cystatin E/M、 tissue inhibitor of met alloproteinase 4、 KIAA1775 (MT-protocad erin) ^ keratin 18、 keratin 19、 smooth muscle myosin heavy chain 11, isoform SM2、 sciell in (SCEL)、 KIAA 0353 I desmuslin (intermediate filament protein) ^ calponin protein - ty rosine-phosphatase Dl、 angiogenin (R ase A family, 5)、 R ase 4、 carbon ic anhydrase isozyme VI (CA6)、 amylase, alpha 2B ; pancreatic^ CMP- N- ace tylneuraminic acid hydroxylase^ Aminomethyltransf erase (glycine cleavag e system protein T)、 Cytochrome P450, subfamily IIIA, polypeptide 5、 al cohol dehydrogenase IB (class I) , beta polypeptide^ FABP7 (fatty acid b inding protein 7)、 FABP4 (Fatty acid binding protein 4)、 KIAA0273 / phy tanoyl-CoA hydroxylase interacting protein apolipoprotein Dヽ apolipopr otein E、 hemoglobin, gamma A, gamma G、 hemoglobin, beta、 mammaglobin 1、 raammaglobm 2、 secretoglobm, family ID, member 2、 delta sleep inducing peptide, immunoreactor beta— catenin— interacting protein ICAT、 GATA3、 forkhead/winged helix - like transcription factor 7 (FKHL7)、 Inhibitor ofArgBP2a (ArgBP2a) s H0X2H mRNA from the Hox2 locus, frizzled-related pr otein, G protein-coupled receptor, family C, group 5, member B, GABA-A receptor pi subunit ^ mesenchyme homeo box 2 (growth arrest-specific hom eo box), keratin 7, tumor-associated calcium signal transducer 1, dioxin-inducible cytochrome P450 (CYP1B1), interleukin 1 receptor, type II, platelet / endothelial cell adhesion molecule (CD31antigen) N GRB2-associa ted binding protein 2, mitogen inducible 2, ransgelin, deleted in live T cancer 1, 8-oxoguanine DNA g 丄 ycosylase, enolase 2, (gamma, neuronal), pinin, desmosome associated protein ^ KIAA0367 gene, KIAA0280 gene, KIAA 1053 protein s KIAA0729 protein, KIAA1467 protein, KIAA0716 protein, hyp othetical gene CG018, hypothetical protein FLJ13612, FLJ90798, DKFZp586 11823, D FZp5640222 s kallikreinl, cystatin E / M, tissue inhibitor of met alloproteinase 4, KIAA1775 (MT-protocad erin) ^ keratin 18, keratin 19, smooth musc le myosin heavy chain 11, isoform SM2, sciell in (SCEL), KIAA 0353 I desmuslin (intermediate filament protein) ^ calponin protein-ty rosine-phosphatase Dl, angiogenin (Rase A family, 5), Rase 4, carbonic anhydrase isozyme VI (CA6), amylase, alpha 2B; pancreatic ^ CMP- N- acetylneuraminic acid hydroxylase ^ Aminomethyltransf erase (glycine cleavag e system protein T), Cytochrome P450, subfamily IIIA, polypeptide 5, al cohol dehydrogenase IB (class I), beta polypeptide ^ FABP7 (fatty acid b inding protein 7), FABP4 (Fatty acid binding protein 4), KIAA0273 / phy tanoyl-CoA hydroxylase interacting protein apolipoprotein D ヽ apolipopr otein E, hemoglobin, gamma A, gamma G, hemoglobin, beta, mammaglobin 1, raammaglobm 2, secretoglobm, family ID, member 2, delta sleep inducing peptide, immunoreactor beta— catenin— interacting protein ICAT, GATA3, forkhead / winged helix-like transcription factor 7 (FKHL7), Inhibitor of
DNA binding 4 (ID4)、 Beta-microseminoprotein isoform a (PSP94) , isofor m b (PSP57)、 testicular inhibin beta- B- subtmit、 TM4SF3 (transmembrane 4 superfamily member 3)、 ITM2A (integral membrane protein 2A)、 claudin 8、 syndecan 4 (amphiglycan, ryudocan) proteolipid protein 1、 apMl (adipose most abundant gene transcript 1)、 rolactin-inducible protein、 HZF9、 s kin-specific protein (xp32)、 Crystallin, alpha B、 Hepatocellular care in oma antigen gene 520、 Purkinje cell protein 4 (PCP4)、 141H5 cyclin Dl、 TRIM2 (tripartite motif-containing 2)、 metallothionein IV (MTIV)、 trans membrane 4 superfamily member 11 (plasmolipin) N DKFZp434A202s KIAA0471、 KI 0450, KIAA0633, KIAA0456N Clorf21、 および DKFZp761F2014 DNA binding 4 (ID4), Beta-microseminoprotein isoform a (PSP94), isofor mb (PSP57), testicular inhibin beta- B-subtmit, TM4SF3 (transmembrane 4 superfamily member 3), ITM2A (integral membrane protein 2A), claudin 8, syndecan 4 (amphiglycan, ryudocan) proteolipid protein 1, apMl (adipose most abundant gene transcript 1), rolactin-inducible protein, HZF9, skin-specific protein (xp32), Crystallin, alpha B, Hepatocellular care in oma antigen gene 520, Purkinje cell protein 4 (PCP4), 141H5 cyclin Dl, TRIM2 (tripartite motif-containing 2), metallothionein IV (MTIV), trans membrane 4 superfamily member 11 (plasmolipin) N DKFZp434A202 s KIAA0471, KI 0450, KIAA0633, KIAA0456 N Clorf21, And DKFZp761F2014
i ii) 以下の遺伝子からなる、 乾癬患者の無疹部における発現レベルが健常者 の発現レベルに比べて高い指標遺伝子群： platelet factor 4 (PF4)、 actin, g anma 2, smooth muscle, enteric^ interferon (alpha, beta and omega) rece ptor 2、 DNA topoisomerase I、 CYP3A4、 cycl in-dependent kinase 2、 vascula r endothelial growth factor~D、 ABL1、 adducin 1 (alpha) isoform c、 KLRC3、 RAB2、 l-acylglycerol-3-phosphate 0-acyl transferase 2、 tryptase, alpha^ homolog of Yeast RRP4、 MCM3、 hemoglobin, delta、 KIM1089、 zinc finger p rotein 44 (KOX 7) arylacetamide deacetylase (esterase)、 synuclein, gam mas elastase 2, neutrophil, CYP3A5、 FCGR3A (CD16)、 likely ortholog of m ouse neuralin 1、 pyruvate carboxylase^ 2' , 5' -oligoadenylate synthetase 1、 muscle RAS oncogene homology butyrophilin, subfamily 3， member A2、 c onnective tissue activation peptide III、 Arg/Abl - interacting protein Ar gBP2、 FLJ33034、 calpain 3、 bleomycin hydrolase, desmuslin、 TAF6L、 ESTs (Accession No. AW043812) , FLJ22269, keratin 7、 scaffold attachment fact or B、 KIM0346、 interferon, alpha - inducible protein 27、 bridging integr ator 1、 smooth muscle myosin heavy chain^ hemoglobin, alpha 1、 sickle c ell beta - globin、 beta-globin (HBB)、 A - gamma globin、 carboxypeptidase M、 HCR (a— helix coiled- coil rod homologue)、 nuclear receptor subfamily 1， group H, member 2、 ESTs, Moderately similar to 2004399A chromosomal pro tein、 runt-related transcription factor 1、 および KI 0664 protein i ii) An index gene group consisting of the following genes, whose expression level in the rash area of psoriatic patients is higher than that in healthy subjects: platelet factor 4 (PF4), actin, ganma 2, smooth muscle, enteric ^ interferon (alpha, beta and omega) receptor 2, DNA topoisomerase I, CYP3A4, cycl in-dependent kinase 2, vascula r endothelial growth factor ~ D, ABL1, adducin 1 (alpha) isoform c, KLRC3, RAB2, l-acylglycerol-3-phosphate 0-acyl transferase 2, tryptase, alpha ^ homolog of Yeast RRP4, MCM3, hemoglobin, delta, KIM1089 , zinc finger p rotein 44 (KOX 7) arylacetamide deacetylase (esterase), synuclein, gam ma s elastase 2, neutrophil, CYP3A5, FCGR3A (CD16), likely ortholog of m ouse neuralin 1, pyruvate carboxylase ^ 2 ', 5' - oligoadenylate synthetase 1, muscle RAS oncogene homology butyrophilin, subfamily 3, member A2, conductive tissue activation peptide III, Arg / Abl-interacting protein Ar gBP2, FLJ33034, calpain 3, bleomycin hydrolase, desmuslin, TAF6L, ESTs (Accession No.AW043812 ), FLJ22269, keratin 7, scaffold attachment fact or B, KIM0346, interferon, alpha-inducible protein 27, bridging integrator 1, smooth muscle myosin heavy chain ^ hemoglobin, alpha 1, sickle cell beta-globin, beta-globin ( HBB), A-gamma globin, carboxypept idase M, HCR (a- helix coiled- coil rod homologue), nuclear receptor subfamily 1, group H, member 2, ESTs, Moderately similar to 2004399A chromosomal protein, runt-related transcription factor 1, and KI 0664 protein
iv) 以下の遺伝子からなる、 乾癬患者の無疹部における発現レベルが健常者 の発現レベルに比べて低い指標遺伝子群： H2B histone family, member G、 cho linergic receptor, nicotinic, beta polypeptide 4、 related to the N term inus of tre、 laminin, gamma 2 isoform b、 interleukin 8、 Kruppel - like fa ctor 4 (gut) Alstrom syndrome 1、 occludin、 c-jun proto oncogene^ jun-Bs c-fos、 G0S3 / Fos-B、 c-myc oncogenes AREB6、 ATF3 (activating transcript ion factor 3)、 ETR101、 ZFP36 (zinc finger protein 36)ゝ GRO- beta、 WAF1 I cycl in-dependent kinase inhibitor 1A (p21, Cipl)、 interleukin 6 (inter feron, beta 2)、 CL 100 / dual specificity phosphatase 1、 cyclooxygenas e - 2 (hCox - 2)、 dual specificity phosphatase 2、 holocarboxylase synthetas 3 7 5[ ' ：：: iv) An index group consisting of the following genes, whose expression levels in the rash area of psoriatic patients are lower than those in healthy subjects: H2B histone family, member G, cholinergic receptor, nicotinic, beta polypeptide 4, related to the N term inus of tre, laminin, gamma 2 isoform b, interleukin 8, Kruppel-like factor 4 (gut) Alstrom syndrome 1, occludin, c-jun proto oncogene ^ jun-B s c-fos, G0S3 / Fos- B, c-myco oncogene s AREB6, ATF3 (activating transcript ion factor 3), ETR101, ZFP36 (zinc finger protein 36) ゝ GRO-beta, WAF1 I cycl in-dependent kinase inhibitor 1A (p21, Cipl), interleukin 6 ( inter feron, beta 2), CL 100 / dual specificity phosphatase 1, cyclooxygenas e-2 (hCox-2), dual specificity phosphatase 2, holocarboxylase synthetas 3 7 5 [':::
e、 beta - 2 - adrenergic receptor ^ BL34 / regulator of G - protein signalling 1、 GEM (GTP binding protein overexpressed in skeletal muscle)、 amphire gulin (AR)、 nuclear receptor subfamily 4， group A, member 2、 TR3 (nucle ar receptor subfamily 4， group A, member 1)、 N0T、 glucose transporter - li ke protein- III (GLUT3)、 GADD45B (growth arrest and DNA- damage - inducible, beta) s tumor necrosis factor alpha inducible protein A20、 CYR61、 APR (ATL- derived PMA- responsive gene) ADP-ribosylation factor-like 7、 T54 protein H2B histone family, member H、 clone 23933、 およぴ KIAA0924 3 3 . i)の指標遺伝子群カ、 cellular retinoic acid binding protein 2、 pro teasome (prosome, macropain) activator subunit 2、 interferon induced 6-16 protein^ heat shock 70kDa protein 4、 flap structure - specific end onuclease 1、 NME1、 cyclin— dependent kinase inhibitor 3、 ubiquitin-con jugating enzyme E2C、 calreticulin^ CDC2 gene、 RAN、 liver arginase (AR Gl)、 connexin 43 (GJAl, Cx43)、 interleukin 1 receptor antagonist^ AT P- binding cassette, sub-family A (ABCl) , member 12、 M - phase phosphopr otein 6、 creatine kinase, mitochondrial 1、 Nedd4 binding protein 1、 s olute carrier family 7， member 5、 acid phosphatase, prostate、 plakoph ilin 1、 UDP glycosyltransf erase 1 family, polypep ide A4、 ATPase, H+/ K+ transporting, nongastric, alpha po丄 ypeptide、 cytoskeleton-associat ed protein 4、 glucosidase, beta; acidN interferon-inducible 56 Kd pro teinN low density lipoprotein receptor transglutaminase 3、 arachidon ate 12 - lipoxygenase, 12R type、 CYP7B1、 tripartite motif-containing 14、 hypothetical protein FLJT21168、 neme oxygenase (decycling) 1、 S100 cal cium binding protein P、 gene from PAC 747L4、 SAM domain and HD domain 1、 arylsulfatase F、 potassium inwardly-rectifying channel, subfamily J, member 15、 BUBl budding uninhibited by benzimidazoles 1 homolog b eta (yeast)、 SPllO nuclear body protein isoform b、 guanylate binding protein 1 (GBP1)、 G 2 ganglioside activator proteins complement facto r B preproproteinx squalene epoxidase^ solute carrier family 5 (sodiu m/glucose cotransporter) , member 1、 ZfflO interactor Zwint、 kallikreine, beta-2-adrenergic receptor ^ BL34 / regulator of G-protein signaling 1, GEM (GTP binding protein overexpressed in skeletal muscle), amphire gulin (AR), nuclear receptor subfamily 4, group A, member 2, TR3 (nucle ar receptor subfamily 4, group A, member 1), N0T, glucose transporter-liquid protein-III (GLUT3), GADD45B (growth arrest and DNA- damage-inducible, beta) s tumor necrosis factor alpha inducible protein A20, CYR61, APR (ATL-derived PMA-responsive gene) ADP-ribosylation factor-like 7, T54 protein H2B histone family, member H, clone 23933, and KIAA0924 33.i) indicator genes, cellular retinoic acid binding protein 2, pro teasome (prosome, macropain) activator subunit 2, interferon induced 6-16 protein ^ heat shock 70kDa protein 4, flap structure-specific end onuclease 1, NME1, cyclin—dependent kinase inhibitor 3, ubiquitin-con jugating enzyme E2C, calreticulin ^ CDC2 gene, RAN, liver arginase (AR Gl), connexin 43 (GJAl, Cx43), interleukin 1 receptor antagonist ^ AT P-binding cassette, sub-family A (ABCl), member 12, M-phase phosphoprotein 6, creatine kinase, mitochondrial 1, Nedd4 binding protein 1 , Solute carrier family 7, member 5, acid phosphatase, prostate, plakophilin 1, UDP glycosyltransf erase 1 family, polypepide A4, ATPase, H + / K + transporting, nongastric, alpha po 丄 ypeptide, cytoskeleton-associat ed protein 4, glucosidase, beta; acid N interferon-inducible 56 Kd pro tein N low density lipoprotein receptor transglutaminase 3, arachidon ate 12-lipoxygenase, 12R type, CYP7B1, tripartite motif-containing 14, hypothetical protein FLJT21168, neme oxygenase (decycling) 1, S100 cal cium binding protein P, gene from PAC 747L4, SAM domain and HD domain 1, arylsulfatase F, potassium inwardly-rectifying channel, subfamily J, member 15, BUBl budding uninhibited by benzimidazoles 1 homolog b eta (yeast), SPllO nuclear body protein isoform b, guanylate binding protein 1 (GBP1), G 2 ganglioside activator protein s complement factor B preproprotein x squalene epoxidase ^ solute carrier family 5 (sodiu m / glucose cotransporter), member 1, ZfflO interactor Zwint, kallikrein
13、 interferon regulatory factor 7、 N-myc (and STAT) interactor^ Sta t2、 tripartite motif-containing 22、 kinesin— like 6、 kallikrein 10、 ri bonucleotide reductase 2 polypeptide^ chromosome 1 open reading fram e 29、 Sjogren syndrome antigen Al、 gamma-glutamyl hydrolase lymphocy te antigen 6 complex, locus E、 in erleukin-1 receptor antagonist^ int erf eron - induced protein 44、 lectin, galactoside-binding, soluole, 3 b inding protein^ retinoblastoma binding protein 6、 vipirin^ interf ero n - induced protein with tetratr i copept i de repeats 4、 S100 calcium bind ing protein A12 (calgranulin C)、 bone marrow stromal cell antigen 2、 chromosome 20 open reading frame 1、 aquaporin. 3、 cystatin A (stef in A)、 KIAA0186、 retinoblastoma— associated protein HEC、 NS1— associated p rotein 1、 topoisomerase (DNA) II alpha 170kDaN H2A histone family, me mber X、 chemokine exodus— 1、 pituitary tumor - transforming 1、 SCO cytoc hrome oxidase deficient homo log 2 (yeast) s CDC28 protein kinase regul atory subunit 2、 kinesin— like 1、 histidine a脆 onia - lyase、 hypothetica 1 rotein FLJ10534、 cyclin El、 chromosome 1 open reading frame 34、 ce llular retinoic acid binding protein 2、 TTK protein kinase^ acid phos phatase, prostate^ interleukin 8 receptor beta (IL8RB) RAB27A、 MX2、 thymidine kinase 1、 interferon-inducible 56 Kd protein^ serum/glucoco rticoid regulated kinase^ EphA2、 nitric oxide synthase 2A、 plasminoge n activator, tissue type、 GM2 ganglioside activator protein^ KIAA0963 proteinN kallikrein 13、 ATPase, Class V， type 10B、 および GARTから選 択されたいずれかの遺伝子である請求項 3 2に記載の方法。 13, interferon regulatory factor 7, N-myc (and STAT) interactor ^ stat2, tripartite motif-containing 22, kinesin—like 6, kallikrein 10, ri bonucleotide reductase 2 polypeptide ^ chromosome 1 open reading fram e 29, Sjogren syndrome antigen Al, gamma-glutamyl hydrolase lymphocy te antigen 6 complex, locus E, in erleukin-1 receptor antagonist ^ int erferon-induced protein 44, lectin, galactoside-binding, soluole, 3b inding protein ^ retinoblastoma binding protein 6, vipirin ^ interf ero n-induced protein with tetratr i copept i de repeats 4, S100 calcium binding protein A12 (calgranulin C), bone marrow stromal cell antigen 2, chromosome 20 open reading frame 1, aquaporin. 3, cystatin A (stef in A ), KIAA0186, retinoblastoma-associated protein HEC, NS1-associated protein 1, topoisomerase (DNA) II alpha 170kDa N H2A histone family, member X, chemokine exodus-1, pituitary tumor-transforming 1, SCO cytochrome oxidase deficient homo log 2 (yeast) s CDC28 protein kinase regulatory subunit 2, kinesin-- like 1, histidine a brittle onia-lyase, hypothetica 1 rotein FLJ10534, cyclin El, chromosome 1 open reading frame 34, ce llular retinoic acid binding protein 2, TTK protein kinase ^ acid phos phatase, prostate ^ interleukin 8 receptor beta (IL8RB) RAB27A, MX2, thymidine kinase 1, interferon-inducible 56 Kd protein ^ serum / glucocorticoid regulated kinase ^ EphA2, nitric oxide synthase 2A, plasminogen n activator, tissue type, GM2 ganglioside activator protein ^ KIAA0963 protein N kallikrein 13, ATPase, Class V, type 10B, and GART 33. The method according to claim 32, which is any of the selected genes.
4 · の指標遺 子群力 ¾ヽ catnepsin C、 airway trypsin - like proteaseゝ se rine protease- like proteinゝ protease M、 trypsinogen IV b - form、 neutro phil gelatinase associated lipocalinゝ squamous cell carcinoma antigen -serine protease inhibitor s squamous cell carcinoma antigen 2 (SCCA2)、 mononcyte/neutrophil elastase inhibitor alpha 1- antitrypsin elafin、 inter丄 eukin - 7 receptor ^ interleukin 4 receptor^ platelet-derived endo thelial cell growth factor s pre - B cell enhancing factor (PBEF)ヽ alter native activated macrophage specific CC chemokine 1、 lactotransferrin melanoma growth stimulatory activity (MGSA) / Gro alpha psoriasin (S 100A7)、 MRP- 8 (S100A8)、 MRP- 14(S100A9)、 CaN19 (S100A2) , p cadherin, 13 0-kD pemphigus vulgaris antigen / Desmoglein 3、 desmocollins type 2bヽ CD24 signal transducerヽ 0A3 antigenic surface determinant / CD47、 mon ocy e/ macrophage I g-r elated receptor MIR- 7 / CD85、 lyn、 protein tyros ine phosphatase, receptor type, E isoforml, 2、 tartrate - resistant acid phosphatase type 5、 cholesterol 25-hydroxylases Phospholipid scrambl ase 1、 manganese superoxide dismutase (EC 1· 15· 1· 1)、 uridine phosphor ylase、 aldose reductase - like peptide、 2， , 5， oligoadenylate synthetase isoform E16, E18、 2'， 5， oligoadenylate synthetase 2 isoforra p69, p71、 L-kynurenine hydrolase^ purine nucleoside phosphorylase (PNP; EC 2. 4. 2· 1)、 2， , 5， oligoadenylate synthetase- like (59 kDa isoform)、 cytokera tin 17、 keratin 6A、 keratin 16、 myosin VA (heavy polypeptide 12， myox in 、 Small proline - rich protein SPRK、 small proline- rich protein 2A、 small proline -: rich protein IB (cornifin) N involucrin^ interferon-indu cible protein p78 (MX1)、 interferon- induced 17- kDa/15- kDa protein^ p2 7, interferon - alpha— inducible protein 27、 regulator of G— protein sign ailing 20、 STAT cyclin B、 proto - oncogene (Wnt - 5 、 beta defensin 2 (HBD2)、 KIAA0101, tumor suppressing sub transferable candidate 3 (TSSC 3)、 heparin binding protein (HBpl7) ノ FGF- BP1、 およぴ transcobalamin I から選択されたいずれかの遺伝子である請求項 3 2に記載の方法。 4-indicators heritage element group power ¾ヽcatnepsin C, airway trypsin - like proteaseゝse rine protease- like proteinゝprotease M, trypsinogen IV b - form , neutro phil gelatinase associated lipocalinゝsquamous cell carcinoma antigen -serine protease inhibitor s squamous cell carcinoma antigen 2 (SCCA2), mononcyte / neutrophil elastase inhibitor alpha 1-antitrypsin elafin, inter 丄 eukin-7 receptor ^ interleukin 4 receptor ^ platelet-derived endo thelial cell growth factor s pre-B cell enhancing factor (PBEF) ヽalter native activated macrophage specific CC chemokine 1, lactotransferrin melanoma growth stimulatory activity (MGSA) / Gro alpha psoriasin (S 100A7), MRP-8 (S100A8), MRP-14 (S100A9), CaN19 (S100A2), p cadherin, 130 -kD pemphigus vulgaris antigen / Desmoglein 3, desmocollins type 2b ヽ CD24 signal transducer ヽ 0A3 antigenic surface determinant / CD47, mon ocy e / macrophage I gr elated receptor MIR- 7 / CD85, lyn, protein tyros ine phosphatase, recep tor type, E isoforml, 2, tartrate-resistant acid phosphatase type 5, cholesterol 25-hydroxylase s Phospholipid scramblase 1, manganese superoxide dismutase (EC 1.15.1.1.1), uridine phosphor ylase, aldose reductase-like peptide, 2,, 5, oligoadenylate synthetase isoform E16, E18, 2 ', 5, oligoadenylate synthetase 2 isoforra p69, p71, L-kynurenine hydrolase ^ purine nucleoside phosphorylase (PNP; EC 2.4.2.1), 2,, 5 , Oligoadenylate synthetase- like (59 kDa isoform), cytokera tin 17, keratin 6A, keratin 16, myosin VA (heavy polypeptide 12, myox in, Small proline-rich protein SPRK, small proline-rich protein 2A, small proline-: rich protein IB (cornifin) N involucrin ^ interferon-inducible protein p78 (MX1), interferon- induced 17-kDa / 15- kDa protein ^ p2 7, interferon-alpha— inducible protein 27, regulator of G— protein sign ailing 20, STAT cyclin B, proto-oncogene (Wnt-5, beta defensin 2 (HBD2), KIAA0101, tumor suppressing sub transferable candidate 3 (TSSC 3), heparin binding protein (HBpl7) FGF-BP1, and transcobalamin The method according to claim 32, which is any gene selected from I.
5 . ii)の 標逾 十 カ、 actin, alpha 2, smooth muscle, aorta、 actin, gamma 2, smooth muscle, enter ic^ cisplatin resistance associated^ gr owth arrest-specific 6、 insulin-like growth factor binding protein 6 (IGFBP6)、 insulin induced protein 1 (INSIGl) N PDGF receptor beta-like tumor suppressor (PRLTS)、 R - ras、 sarcospan (Kras oncogene- associated gene) s fibroblast growth factor (FGF) receptor - 1、 fibronectin 1 isof orm 1 preproprotein^ chromosome 21 open reading frame 25、 seven in ab sentia homolog 1 (Drosophila)、 fatty acid desaturase 1、 fatty acid de saturase 2、 Rho - related BTB domain containing 3、 matrilin 2、 adipose specific 2、 LIM protein^ LIM domain binding 2 / CLIM1、 myosin light c hain kinase (MLCK)、 myosin, light polypeptide 9， regulatory、 tropomyo sin 1 (alpha) s cysteine -: rich protein 1 (intestinal) N reversion— induci ng一 cysteine— rich protein with kazal motifs、 amine oxidase, copper con taining 3 (vascular adhesion protein 1)、 cytochrome c oxidase subunit Vila polypeptide 1 (muscle)、 cheraokine (C-C motif) ligand 14、 ocular development-associated geheゝ ephrin - B2、 Na, K-ATPase subunit alpha 2 (ATP1A2)、 ATPase, Ca++ transporting, ubiquitous^ aquaporin 9、 pleiotr ophin、 cadherin 19, type 2、 WNT inhibitory factor 1、 WNTl inducible s ignaling pathway protein 2ヽ 丄丄ー beta一 hydroxysteroid dehydrogenase (HSD 11)、 myelin basic protein (MBP)ヽ pro- galaninヽ dihydropyrimidirmse - lik e 3、 glypican - 4 (GPC4)、 acetylserotonin O-methyltransf erase-like, syn uclein, gammaゝ connective tissue growth facto:r、 breast cancer anti— es trogen resistance 3、 heat shock 70kDa protein 2、 ets variant gene 1、 cAMP— dependent protein kinase subunit RII - beta、 microtubule - associate d protein, RP/EB family, member 2、 ATP - binding cassette, sub-family C (CFTR/MRP) , member 3、 transmembrane 4 superfamily member 2、 AXL rece ptor tyrosine kinase、 phospholamban^ Fc fragment of IgG binding prote in、 microsomal glutathione S - transferase 3、 DEPP (decidual protein in duced by progesterone)、 Arg/Aol-interacting protein ArgBP2a (ArgBP2a)ヽ H0X2H mRNA from the Hox2 locus、 frizzled - related protein G protein-c oupled receptor, family C, group 5, member B、 GABA-A receptor pi subu nit、 mesenchyme homeo box 2 (growth arrest-specific homeo box) kerat in 7、 tumor-associated calcium signal transducer 1、 dioxin— inducible cytochrome P450 (CYP1B1)、 interleukin 1 receptor, type II、 platelet/e ndothelial cell adhesion molecule (CD31antigen)、 GRB2- associated bind ing protein 2、 mitogen inducible 2、 transgelin^ deleted in liver cane er 1、 8-oxoguanine DNA glycosylase、 enolase 2, (gamma, neuronal) x pin in, desmosome associated protein^ KIAA0367 gene、 KIAA0280 gene、 KIAAl 053 protein, KIAA0729 protein, KIAA1467 protein、 KIAA0716 protein, hy pothetical gene CG018、 hypothetical protein FLJ13612、 FLJ90798、 DKFZp 58611823、 および DKFZp5640222から選択されたいずれかの遺伝子である請求 項 3 2に記載の方法。 " 5.ii) actin, alpha 2, smooth muscle, aorta, actin, gamma 2, smooth muscle, enter ic ^ cisplatin resistance associated ^ gr owth arrest-specific 6, actin, alpha 2, smooth muscle, aorta, insulin-like growth factor binding protein 6 (IGFBP6), insulin induced protein 1 (INSIGl) N PDGF receptor beta-like tumor suppressor (PRLTS), R-ras, sarcospan (Kras oncogene- associated gene) s fibroblast growth factor (FGF) receptor-1, fibronectin 1 isof orm 1 preproprotein ^ chromosome 21 open reading frame 25, seven in ab sentia homolog 1 (Drosophila), fatty acid desaturase 1, fatty acid de saturase 2, Rho-related BTB domain containing 3, matrilin 2, adipose specific 2, LIM protein ^ LIM domain binding 2 / CLIM1, myosin light c hain kinase (MLCK), myosin, light polypeptide 9, regulatory, tropomyo sin 1 (alpha) s cysteine-: rich protein 1 (intestinal) N reversion— inducin ng cysteine— rich protein with kazal motifs, amine oxidase, copper con taining 3 (vascular adhesion pr otein 1), cytochrome c oxidase subunit Vila polypeptide 1 (muscle), cheraokine (CC motif) ligand 14, ocular development-associated gehe ゝ ephrin-B2, Na, K-ATPase subunit alpha 2 (ATP1A2), ATPase, Ca ++ transporting, ubiquitous ^ aquaporin 9, pleiotr ophin, cadherin 19, type 2, WNT inhibitory factor 1, WNTl inducible s ignaling pathway protein 2 ヽ -beta-hydroxysteroid dehydrogenase (HSD 11), myelin basic protein (MBP) ヽ pro-galanin ヽdihydropyrimidirmse-lik e 3, glypican-4 (GPC4), acetylserotonin O-methyltransf erase-like, syn uclein, gamma ゝ connective tissue growth facto: r, breast cancer anti-es trogen resistance 3, heat shock 70kDa protein 2, ets variant gene 1, cAMP—dependent protein kinase subunit RII-beta, microtubule-associate d protein, RP / EB family, member 2, ATP-binding cassette, sub-family C (CFTR / MRP), member 3, transmembrane 4 superfamily member 2, AXL receptor tyrosine kinase, phospholamban ^ Fc fragment of IgG binding protein, microsomal glutathione S-transferase 3, DEPP (decidual protein in duced by progesterone), Arg / Aol- interacting protein ArgBP2a (ArgBP2a) ヽ H0X2H mRNA from the Hox2 locus, frizzled-related protein G protein-coupled receptor, family C, group 5, member B, GABA-A receptor pi subunit, mesenchyme homeo box 2 (growth arrest- specific homeo box) kerat in 7, tumor-associated calcium signal transducer 1, dioxin- inducible cytochrome P450 (CYP1B1), interleukin 1 receptor, type II, platelet / endothelial cell adhesion molecule (CD31antigen), GRB2-associated bind ing protein 2 , Mitogen inducible 2 , Transgelin ^ deleted in liver caneer 1, 8-oxoguanine DNA glycosylase, enolase 2, (gamma, neuronal) x pin in, desmosome associated protein ^ KIAA0367 gene, KIAA0280 gene, KIAAl 053 protein, KIAA0729 protein, KIAA1467 protein, KIAA0716 protein 33. The method according to claim 32, wherein the gene is any one selected from the group consisting of: hypothetical gene CG018, hypothetical protein FLJ13612, FLJ90798, DKFZp58611823, and DKFZp5640222. "
6 . ii)の指標遺伝子群が、 kallikreinl、 cystatin E/M, tissue inhibitor of metalloproteinase 4、 KIAAl 775 (MT-protocadherin)、 keratin 18、 kera tin 19、 smooth muscle myosin heavy chain 11, isoform SM2、 sciellin (S CEU、 KIAA0353 I desmuslin (intermediate filament protein)、 calponinl、 protein- tyrosine- phosphatase Dls angiogenic (RNase A family, 5)、 RNa se 4、 carbonic anhydrase isozyme VI (CA6)、 amylase, alpha 2B; pancrea 3 8 θΓ 7 The indicator genes of 6.ii) are kallikreinl, cystatin E / M, tissue inhibitor of metalloproteinase 4, KIAAl775 (MT-protocadherin), keratin 18, kera tin 19, smooth muscle myosin heavy chain 11, isoform SM2, sciellin ( S CEU, KIAA0353 I desmuslin (intermediate filament protein), calponinl, protein- tyrosine- phosphatase Dl s angiogenic (RNase A family, 5), RNa se 4, carbonic anhydrase isozyme VI (CA6), amylase, alpha 2B; pancrea 3 8 θΓ 7
tic、 CMP-N-acetylneuraminic acid hydroxylase^ Aminomethyl transferase (glycine cleavage system protein T)、 Cytochrome P450, subfamily IIIA, polypeptide 5、 alcohol dehydrogenase IB (class 1)， beta polypeptide^ FABP7 (fatty acid binding protein 7)、 FABP4 (Fatty acid binding prote in 4)、 KIAA0273 / phytanoyl-CoA hydroxylase interacting protein^ apol ipoprotein D、 apolipoprotein E、 hemoglobin, gamma A, gamma G、 hemoglo bin, beta、 mammaglobin 1、 raammaglobin 2、 secretoglobin, family ID, me mber 2、 delta sleep inducing peptide, i應 unoreactor、 beta-catenin-int eracting protein ICAT、 GATA3、 forkhead/winged helix-like transcriptio n factor 7 , (FKHL7)、 Inhibitor of DNA binding 4 (ID4)、 Beta-mi croserain oprotein isoform a (PSP94) , isoform b (PSP57) testicular inhibin bet a-B— subunit、 TM4SF3 (transmembrane 4 superfaniily member 3)、 ITM2A (in tegral membrane protein 2A)、 claudin 8、 syndecan 4 (amphiglycan, ryud ocan) ^ proteolipid protein 1、 apMl (adipose most abundant gene trans cr ipt 1)、 prolactin - inducible protein^ HZF9、 skin-specific protein (xp3 2)、 Crystallin, alpha B、 Hepatocellular carcinoma antigen gene 520、 P urkinje cell protein 4 (PCP4)、 141H5、 cyclin Dl、 TRIM2 (tripartite mo t if - containing 2)、 metallothionein IV (MTIV)、 transmembrane 4 superfa mily member 11 (plasmolipin)、 DKFZp434A202、 KIAA0471, KIM0450、 KIAAO 633、 KIAA0456, Clorf21 および DKFZp761F2014から選択されたいずれかの 遺伝子である請求項 3 2に記載の方法。 tic, CMP-N-acetylneuraminic acid hydroxylase ^ Aminomethyl transferase (glycine cleavage system protein T), Cytochrome P450, subfamily IIIA, polypeptide 5, alcohol dehydrogenase IB (class 1), beta polypeptide ^ FABP7 (fatty acid binding protein 7), FABP4 (Fatty acid binding protein 4), KIAA0273 / phytanoyl-CoA hydroxylase interacting protein ^ apol ipoprotein D, apolipoprotein E, hemoglobin, gamma A, gamma G, hemoglo bin, beta, mammaglobin 1, raammaglobin 2, secretoglobin, family ID, me mber 2, delta sleep inducing peptide, iio unoreactor, beta-catenin-interacting protein ICAT, GATA3, forkhead / winged helix-like transcription factor 7,, (FKHL7), Inhibitor of DNA binding 4 (ID4), Beta-mi croserain oprotein isoform a (PSP94), isoform b (PSP57) testicular inhibin bet aB--subunit, TM4SF3 (transmembrane 4 superfaniily member 3), ITM2A (integral membrane protein 2A), claudin 8, syndecan 4 (amphiglycan, ryud ocan) ^ proteolipid protein 1, apM l (adipose most abundant gene trans cr ipt 1), prolactin-inducible protein ^ HZF9, skin-specific protein (xp3 2), Crystallin, alpha B, Hepatocellular carcinoma antigen gene 520, Purkinje cell protein 4 (PCP4), 141H5, cyclin Dl, TRIM2 (tripartite mo t if-containing 2), metallothionein IV (MTIV), transmembrane 4 superfa mily member 11 (plasmolipin), DKFZp434A202, KIAA0471, KIM0450, KIAAO 633, KIAA0456, Clorf21 and DKFZp761F2014 33. The method according to claim 32, wherein the gene is:
7 . iii)の指標遺伝子群が、 platelet factor 4 (PF4)、 actin, gamma 2, sm ooth muscle, entericヽ interferon (alpha, beta and omega) receptor 2、 DNA topoisomerase I、 CYP3A4、 cycl in-dependent kinase 2、 vascular endo thelial growth factor- D、 ABL1、 adducin 1 (alpha) isoform c、 KLRC3、 RA B2、 l-acylglycerol-3-phosphate 0-acyltransf erase 2、 tryptase, alphaN 3 8 1 ' '' 一■' ! ニ The indicator genes of 7.iii) are platelet factor 4 (PF4), actin, gamma 2, smoooth muscle, enteric ヽ interferon (alpha, beta and omega) receptor 2, DNA topoisomerase I, CYP3A4, cycl in-dependent kinase 2, vascular endothelial growth factor- D, ABL1, adducin 1 (alpha) isoform c, KLRC3, RA B2, l-acylglycerol-3-phosphate 0-acyltransf erase 2, tryptase, alpha N 3 8 1 '''single■'! D
homo log of Yeast RRP4、 MCM3、 hemoglobin, delta. KIAA1089S zinc finger protein 44 (KOX 7)、 arylacetamide deacetylase (esterase) s synuclein, ga匪、 elastase 2, neutrophil, CYP3A5、 FCGR3A (CD 16) s likely ortholo g of mouse neural in 1、 pyruvate carboxylase^ 2，， 5' - oligoadeny丄 ate syn thetase 1、 muscle RAS oncogene homology butyrophilin, subfamily 3, me mber A2、 connective tissue activation peptide III、 Arg/Abl-interact in g protein ArgBP2、 FLJ33034、 calpain 3、 bleomycin hydrolase、 desmuslin、 TAF6Lゝ ESTs (Accession No. ATO43812)、 FLJ22269、 keratin 7、 scaffold at tachraent factor B、 KIM0346、 interferon, alpha - inducible protein 27、 bridging integrator 1、 およぴ smooth muscle myosin heavy chain 力 b選 択されたいずれかの遺伝子である請求項 3 2に記載の方法。 homo log of Yeast RRP4, MCM3, hemoglobin, delta.KIAA1089 S zinc finger protein 44 (KOX 7), arylacetamide deacetylase (esterase) s synuclein, ga marauder, elastase 2, neutrophil, CYP3A5, FCGR3A (CD 16) s likely ortholo g of mouse neural in 1, pyruvate carboxylase ^ 2 ,, 5 '-oligoadeny 丄 ate syn thetase 1, muscle RAS oncogene homology butyrophilin, subfamily 3, member A2, connective tissue activation peptide III, Arg / Abl-interact in g protein ArgBP2 , FLJ33034, calpain 3, bleomycin hydrolase, desmuslin, TAF6L ゝ ESTs (Accession No.ATO43812), FLJ22269, keratin 7, scaffold at tachraent factor B, KIM0346, interferon, alpha-inducible protein 27, bridging integrator 1, and ぴ smooth 33. The method according to claim 32, wherein the gene is any of the selected genes.
8 . iii)の指標遺伝子群力 s、 hemoglobin, alpha 1、 sickle cell beta-globi n、 beta-globin (HBB)、 A— gamma globin、 carboxypept i dase M、 HCR (a-heli x coiled - coil rod homologue)、 nuclear receptor subfamily 1， group H, member 2、 ESTs, Moderately similar to 2004399A chromosomal proteinN r unt-related transcription factor 1、 ぉょぴ KIAA0664 protein力 ら選択さ れたいずれかの遺伝子である請求項 3 2に記載の方法。 8.iii) Indicator gene group power s , hemoglobin, alpha 1, sickle cell beta-globin, beta-globin (HBB), A-gamma globin, carboxypept idase M, HCR (a-heli x coiled-coil rod homologue), nuclear receptor subfamily 1, group H, member 2, ESTs, Moderately similar to 2004 399A chromosomal protein N r unt-related transcription factor 1, or KIAA0664 protein. 32. The method according to 2.
9 . iv)の指標逾伝子群；^、 H2B histone family, member G、 cholinergic re ceptor, nicotinic, beta polypeptide 4、 related to the N terminus of t ； re、 laminin, gamma 2 isoform b、 interleukin 8、 Kruppel-1 ike factor 4 (gut)、 Alstrom syndrome 1、 およぴ occludinから選択されたいずれかの遺 伝子である請求項 3 2に記載の方法。  9) iv) Indices from the index: ^, H2B histone family, member G, cholinergic re ceptor, nicotinic, beta polypeptide 4, related to the N terminus of t; re, laminin, gamma 2 isoform b, interleukin 8, The method according to claim 32, wherein the method is any one of genes selected from Kruppel-1 ike factor 4 (gut), Alstrom syndrome 1, and occludin.
0 . iv)の指標遺伝子群が、 C- jun proto oncogene, jun- B、 c- fosゝ G0S3 / F os- B、 c-myc oncogene^ AREB6、 ATF3 (activating transcription factor 3)、 ETR101、 ZFP36 (zinc finger protein 36)、 GRO-beta, WAFl / cyclin- depen dent kinase inhibitor 1A (p21, Cipl)、 interleukin 6 (interferon, beta 2)、 CL 100 I dual specificity phosphatase 1、 cyclooxygenas e-2 (hCox- 2)、 dual specificity phosphatase 2、 holocarboxylase synthetase^ beta - 2 - adrenergic receptor BL34 / regulator of G - protein signalling 1、 GE M (GTP binding protein overexpressed in skeletal muscle)、 amphireguli n (AR)、 nuclear receptor subfamily 4, group A, member 2、 TR3 (nuclear receptor subfamily 4, group A, member 1)、 N0T、 glucose transporter— li ke protein-III (GLUT3)、 GADD45B (growth arrest and DNA- damage - indue ib le， beta)、 tumor necrosis factor alpha inducible protein A20、 CYR61、 APR (ATL-derived PMA - responsive gene) N ADP-ribosylation factor-like 7、 T54 protein, H2B histone family, member H、 clone 23933、 および KI 092 4から選択されたいずれかの遺伝子である請求項 3 2に記載の方法。 The indicator genes of 0.iv) are C-jun proto oncogene, jun-B, c-fos ゝ G0S3 / Fos-B, c-myc oncogene ^ AREB6, ATF3 (activating transcription factor 3), ETR101, ZFP36 ( zinc finger protein 36), GRO-beta, WAFl / cyclin-dependent kinase inhibitor 1A (p21, Cipl), interleukin 6 (interferon, beta 2), CL 100 I dual specificity phosphatase 1, cyclooxygenas e-2 (hCox-2), dual specificity phosphatase 2, holocarboxylase synthetase ^ beta-2-adrenergic receptor BL34 / regulator of G-protein signaling 1, GEM (GTP binding protein overexpressed in skeletal muscle), amphiregulin (AR), nuclear receptor subfamily 4, group A, member 2, TR3 (nuclear receptor subfamily 4, group A, member 1), N0T, glucose transporter—like protein-III (GLUT3 ), GADD45B (growth arrest and DNA- damage-indue ib le, beta), tumor necrosis factor alpha inducible protein A20, CYR61, APR (ATL-derived PMA-responsive gene) N ADP-ribosylation factor-like 7, T54 protein, 33. The method according to claim 32, wherein the gene is any gene selected from H2B histone family, member H, clone 23933, and KI0924.
1 . 伝子の発現レベルを、 cDNAの PCRによって測定する請求項 3 2に記載の 検査方法。  1. The test method according to claim 32, wherein the expression level of the gene is measured by cDNA PCR.
2 . 遺伝子の発現レベルを、 指標遺伝子によってコードされる蛋白質の検出 によって測定する請求項 3 2に記載の検査方法。  3. The test method according to claim 32, wherein the expression level of the gene is measured by detecting a protein encoded by the indicator gene.
3 . 指標遺伝子の塩基配列を含むポリヌクレオチド、 またはその相補鎖に相 補的な塩基配列を有する少なくとも 1 5塩基の長さを有するオリ 'ゴヌクレオ チドからなる、 乾癬検査用試薬であって、 指標遺伝子が請求項 3 2における i)〜iv)のいずれかに記載の群から選択されたいずれかの遺伝子である乾癬検 4 . 指標遺伝子によってコードされる蛋白質を認識する抗体からなる、 乾癬 検査用試薬であって、 指標遺伝子が請求項 3 2における i)〜： ίν)のいずれかに 記載の群から選択されたレ、ずれかの遺伝子である乾癬検查用試薬。  3. A psoriasis test reagent, comprising a polynucleotide containing the nucleotide sequence of the indicator gene or an oligonucleotide having a length complementary to at least 15 nucleotides and having a complementary nucleotide sequence to its complementary strand. A psoriasis test, wherein the gene is any one selected from the group according to any of i) to iv) in claim 32. 4. A psoriasis test, comprising an antibody that recognizes a protein encoded by the indicator gene. 33. A reagent for psoriasis detection, wherein the indicator gene is a gene selected from the group according to any one of i) to ： ν) according to claim 32.
5 . 次の工程を含む、 乾癬の治療薬のスクリーニング方法であって、 指標遺 伝子が請求項 3 2における i)〜iv)のいずれかに記載の群から選択されたいず れかの遺伝子であるスクリーニング方法。 ( 1 ) 指標遺伝子を発現する細胞に候補化合物を接触させる工程、 5. A method for screening a therapeutic agent for psoriasis, comprising the following steps, wherein the indicator gene is any one of the genes selected from the group according to any one of i) to iv) in claim 32: Screening method. (1) contacting a candidate compound with cells expressing the indicator gene,
( 2 ) 前記遺伝子の発現レベルを測定する工程、 および  (2) measuring the expression level of the gene, and
( 3 ) 候補化合物を接触させない対照と比較して、 i)群または i i i)群の指標 遺伝子については前記遺伝子の発現レベルを低下させる化合物を、 また ii) 群または i V)群の指標遺伝子については前記遺伝子の発現レベルを上昇させ る化合物を選択する工程  (3) Compared with a control not contacted with a candidate compound, the index gene of the group i) or iii) is used for a compound that decreases the expression level of the gene, and the marker gene of the group ii) or i Is a step of selecting a compound that increases the expression level of the gene
6 . 細胞が株化皮膚細胞である請求項 4 5に記載の方法。 6. The method according to claim 45, wherein the cells are established skin cells.
7 . 指標遺伝子の塩基配列を含むポリヌクレオチド、 またはその相補鎖に相 補的な塩基配列を有する少なくとも 1 5塩基の長さを有するオリゴヌクレオ チドと、 指標遺伝子を発現する細胞を含む、 乾癬の治療薬侯補化合物をスク リーユングするためのキットであって、 指標遺伝子が請求項 3 2における i)7. A psoriasis containing a polynucleotide containing the nucleotide sequence of the indicator gene, or an oligonucleotide having at least 15 nucleotides in length having a complementary nucleotide sequence to its complementary strand, and a cell expressing the indicator gene. A kit for screening a therapeutic candidate compound, wherein the indicator gene is i) according to claim 32.
〜iv)のいずれかに記載の群から選択されたいずれかの遺伝子であるキット。 8 . 指標遺伝子によってコードされる蛋白質を認識する抗体と、 指標遺伝子 を発現する細胞を含む、 乾癬の治療薬候補化合物をスクリーニングするため のキットであって、 指標遺伝子が請求項 3 2における i；)〜 iv)のいずれかに記 載の群から選択されたいずれかの遺伝子であるキット。 A kit which is any gene selected from the group described in any one of-to iv). 8. A kit for screening a candidate compound for a therapeutic agent for psoriasis, comprising an antibody that recognizes a protein encoded by an indicator gene and a cell that expresses the indicator gene, wherein the indicator gene is i in claim 32; A kit which is any gene selected from the group described in any one of) to iv).
9 . 指標遺伝子または指標遺伝子と機能的に同等な遺伝子の皮膚における発 現強度を上昇させたトランスジヱニック非ヒト脊椎動物からなる乾癬モデル 動物であって、 指標遺伝子が請求項 3 2における i)群おょぴ iii)群に記載の 群から選択されたいずれかの遺伝子であるモデル動物。  9. A psoriatic model animal comprising a transgenic non-human vertebrate with an increased expression intensity in the skin of an indicator gene or a gene functionally equivalent to the indicator gene, wherein the indicator gene is i in claim 32. ) Group iii) A model animal that is any gene selected from the group described in Group iii).
0 . 非ヒト脊椎動物がマウスである請求項 4 9に記载のモデル動物。  0. The model animal according to claim 49, wherein the non-human vertebrate is a mouse.
1 . 指標遺伝子または指標遺伝子と機能的に同等な遺伝子の皮膚における発 現強度を低下させたトランスジエニック非ヒト脊椎動物からなる乾癬モデル 動物であって、 指標遺伝子が請求項 3 2における ii)群および iv)群から選択 されたいずれかの遺伝子であるモデル動物。  1. A psoriatic model animal comprising a transgenic non-human vertebrate animal whose expression intensity in the skin of an indicator gene or a gene functionally equivalent to the indicator gene has been reduced, wherein the indicator gene is ii) in claim 32. A model animal which is any gene selected from the group and iv) group.
2 . 非ヒト脊椎動物がマウスである請求項 5 1に記載のモデル動物。 2. The model animal according to claim 51, wherein the non-human vertebrate is a mouse.
3 . 次の工程を含む、 乾癬の治療薬のスクリーニング方法であって、 指標遺 伝子が請求項 3 2における i)〜： Lv)のいずれかに記載の群から選択されたいず れかの遺伝子、 または指標遺伝子と機能的に同等な遺伝子であるスクリー二 ング方法。 3. A method for screening a therapeutic agent for psoriasis, comprising the following steps, wherein the indicator gene is selected from the group described in any one of i) to Lv) in claim 32: A screening method that is a gene or a gene that is functionally equivalent to an indicator gene.
( 1 ) 指標遺伝子の転写調節領域と、 この転写調節領域の制御下に発現するレ ポータ一遺伝子とを含むベタターを導入した細胞と候補化合物を接触させる 工程、  (1) contacting a candidate compound with a cell into which a betater containing the transcriptional regulatory region of the indicator gene and a reporter gene expressed under the control of the transcriptional regulatory region has been introduced;
( 2 ) 前記レポーター遺伝子の活性を測定する工程、 および  (2) measuring the activity of the reporter gene, and
( 3 ) 候補ィヒ合物を接触させない对照と比較して、 i)群または iii)群の指標 遺伝子については前記レポーター遺伝子の発現レベルを低下させる化合物を、 また ii)群または iv)群の指標遺伝子については前記レポーター遺伝子の発 現レベルを上昇させる化合物を選択する工程、  (3) a compound that reduces the expression level of the reporter gene for the indicator gene of group i) or group iii) as compared to the control without contacting the candidate eh compound, and group ii) or group iv) Selecting a compound that increases the expression level of the reporter gene for the indicator gene;
4 . 次の工程を含む、 乾癬の治療薬のスクリーニング方法であって、 指標遺 伝子が請求項 3 2における i)〜： lv)のいずれかに記載の群から選択されたいず れかの遺伝子、 または指標遺伝子と機能的に同等な遺伝子であるスクリー二 ング方法。  4. A method for screening a therapeutic agent for psoriasis, comprising the following steps, wherein the indicator gene is selected from the group described in any one of i) to lv) in claim 32: A screening method that is a gene or a gene that is functionally equivalent to an indicator gene.
( 1 ) 指標遺伝子によってコードされる蛋白質と候補化合物を接触させる工程、 (1) contacting a protein encoded by the indicator gene with a candidate compound,
( 2 ) 前記蛋白質の活性を測定する工程、 および (2) measuring the activity of the protein, and
( 3 ) 候ネ甫ィヒ合物を接触させない対照と比較して、 i)群または iii)群の指標 遺伝子については前記活性を低下させるィ匕合物を、 また ii)群または iv)群 の指標遺伝子については前記活性を上昇させる化合物を選択する工程  (3) Compared with a control not contacted with the compound, the indicator gene of the group i) or iii) is used as the indicator gene for decreasing the activity, and the group ii) or iv) Selecting a compound that increases the activity for the indicator gene
5 . 請求項 4 5、 請求項 5 3、 および請求項 5 4のいずれかに記載のスクリ 一二ング方法によって得ることができる化合物を有効成分として含有する、 乾癬の治療薬。  5. A therapeutic agent for psoriasis, comprising a compound obtainable by the screening method according to any one of claims 45, 53, and 54 as an active ingredient.
6 . 指標遺伝子、 またはその一部のアンチセンス DNA を有効成分として含む 乾癬の治療薬であって、 指標遺伝子が請求項 3 2における i)または iii)のい ずれかに記載の群から選択されたいずれかの遺伝子である治療薬。 6. A therapeutic agent for psoriasis comprising an indicator gene or a part thereof antisense DNA as an active ingredient, wherein the indicator gene is any of i) or iii) in claim 32. A therapeutic agent that is any gene selected from the group described in any of the above.
7 . 指標遺伝子によってコードされる蛋白質を認識する抗体を有効成分とし て含む、 乾癬の治療薬であって、 指標遺伝子が請求項 3 2における i)または iii)のいずれかに記載の群から選択されたいずれかの遺伝子である治療薬。 8 . 指標遺伝子、 または指標遺伝子によってコードされる蛋白質を有効成分 として含む、 乾癬の治療薬であって、 指標遺伝子が請求項 3 2における ii)ま たは i V)に記載の群から選択されたレ、ずれかの遺伝子である治療薬。 7. A therapeutic agent for psoriasis comprising, as an active ingredient, an antibody that recognizes a protein encoded by an indicator gene, wherein the indicator gene is selected from the group according to any one of i) and iii) in claim 32. Therapeutic agent that is any of the genes identified 8. A therapeutic agent for psoriasis comprising an indicator gene or a protein encoded by the indicator gene as an active ingredient, wherein the indicator gene is selected from the group described in ii) or i V) in claim 32. Tare, a therapeutic drug that is a gene.
9 . 指標遺伝子を測定するためのプローブを固定した乾癬の診断用 DNAチッ プであって、 指標遺伝子が請求項 3 2に記載された i)〜iv)群のいずれかから 選択された少なくとも 1種類の遺伝子である DMチップ。 9. A diagnostic DNA chip for psoriasis having a probe for measuring an indicator gene immobilized thereon, wherein the indicator gene is at least one selected from any of the groups i) to iv) described in claim 32. DM chip which is a kind of gene.
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