WO2004083241A2 - Proteines interagissant avec btc et utilisation de ces proteines - Google Patents

Proteines interagissant avec btc et utilisation de ces proteines Download PDF

Info

Publication number
WO2004083241A2
WO2004083241A2 PCT/JP2004/003699 JP2004003699W WO2004083241A2 WO 2004083241 A2 WO2004083241 A2 WO 2004083241A2 JP 2004003699 W JP2004003699 W JP 2004003699W WO 2004083241 A2 WO2004083241 A2 WO 2004083241A2
Authority
WO
WIPO (PCT)
Prior art keywords
protein
amino acids
sequence
set forth
btc
Prior art date
Application number
PCT/JP2004/003699
Other languages
English (en)
Other versions
WO2004083241A3 (fr
Inventor
Takeshi Sakamoto
Shizu Takeda
Original Assignee
Takeda Pharmaceutical Company Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Publication of WO2004083241A2 publication Critical patent/WO2004083241A2/fr
Publication of WO2004083241A3 publication Critical patent/WO2004083241A3/fr

Links

Classifications

    • 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
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6454—Dibasic site splicing serine proteases, e.g. kexin (3.4.21.61); furin (3.4.21.75) and other proprotein convertases
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/02—Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)

Definitions

  • test compounds may be screened in an in vitro binding assay to identify compounds capable of binding a protein complex of the present invention or BTC or a BTC-interacting protein identified in accordance with the present invention or a homologue, derivative or fragment thereof.
  • a method for detecting, in a sample, a protein complex containing BTC and a polypeptide selected from the group consisting of mLQC243548, mDLK 1 , mPACE4, mBC032073(1598), mTHBS2, mFBLNS, mAK009011, mHRMTlL2, mMATNS, mNDDl, mTASP(459), mINPPSB, mTAKEDAOOS, UBB, mTREXl, mSGT and CAMLG comprising: contacting said sample with an antibody selected from the group consisting of an antibody specific to said protein complex, an antibody specific to BTC and an antibody specific to a protein selected from the group consisting of mLOC243548, mDLKl, mPACE4, mBC032073(1598), mTHBS2, mFBLN5, mAK009011, mHRMTlL2, mMATN3, mNIDl, mT
  • a protein microarray comprising a protein complex having a first protein which is BTC or a homologue or derivative or fragment thereof interacting with a second protein selected from the group consisting of mAKO 13149(453), mLRPl, mTAKEDA002, mBC030871, mLAMBl, mFBNl, mNKD2, mNOTCH4, mSLIT3, mJ02930, mFBLNl , mFBLN2, mBU703758(259), mAK078523(310), mBC039284(996), mADAMTSlO, mAK077302, mNELL2, mTAKEDA007, mCTGF, mNOV, mGRN, UMOD, LRP2(4700), GRN, FBLN1, VWF and LTBP4 or a homologue or derivative or fragment thereof.
  • a second protein selected from the group consisting of mAKO 13149(453),
  • CAMLG also known as CAML
  • calcium modulating ligand, cyclophilin B- binding protein, calcium-modulating cyclophilin ligand or calcium-signal modulating cyclophilin ligand is known lo bind cyclophilin B and regulate calcium signaling in T lymphocytes and other cells.
  • the immunosuppressant drag cyclosporin A blocks a calcium-dependent signal from the T-cell receptor (TCR) that normally leads lo T-cell activation.
  • TCR T-cell receptor
  • cyclosporin A binds and inactivates the key signaling intermediate calcineurin.
  • BTC interacts with mGRN.
  • the sequence having a truncation of up to 31 amino acids at the N-terminus and/or up to 67 (which is obtained by subtracting 111 from 178, the total amino acids number of BTC) amino acids at the C-terminus of the BTC sequence set forth in Figure 1 does not render it unable to interact with UMOD.
  • bifunctional antibodies may also be used, which include those disclosed in Holliger et al, Proc. Nat'l Acad. Sci. USA, 90:6444-6448 (1993); de Kruif et al, J. Biol Chem., 271:7630-7634 (1996); Coloma and Morrison, Nat. Biotechnol, 15:159-163 (1997); Muller et al, FEBS Lett, 422:259-264 (1998); and Muller et al, FEBS Lett., 432:45-49 (1998), all of which are inco ⁇ orated herein by reference.
  • the present invention also provides a method for diagnosing a disease or physiological disorder or a predisposition to the disease or disorder such as diabetes mellitus, hyperlipemia, arteriosclerosis, nephropathy, retinopathy, cardiovascular disease, cancer, fibrosis, autoimmune disease, inflammatory disease, osteoarthritis, osteoporosis, Alzheimer's disease, neurodegenerative disorder and cell proliferative disorder, preferably diabetes mellitus and cancer in a patient by determining whether there is any aberration in the patient with respect to a protein complex having a first protein which is BTC interacting with a second protein selected from the group consisting of GROUPl. The same protein complex is analyzed in a normal individual and is compared with the results obtained in the patient.
  • a disease or physiological disorder or a predisposition to the disease or disorder such as diabetes mellitus, hyperlipemia, arteriosclerosis, nephropathy, retinopathy, cardiovascular disease, cancer, fibrosis, autoimmune disease, inflammatory disease, osteo
  • any protein complex aberration in the patient can be detected.
  • the term "aberration" when used in the context of protein complexes of the present invention means any alterations of a protein complex including increased or decreased level of the protein complex in a particular cell or tissue or organ or the total body, altered localization of the protein complex in cellular compartments or in locations of a tissue or organ, changes in binding affinity of an interacting protein member of the protein complex, mutations in an interacting protein member or the gene encoding the protein, and the like.
  • the term "aberration” is used in a relative sense. Thai is, an aberration is relative lo a normal individual.
  • Antibodies immunoreactive with both an individual interacting protein member and a protein complex containing the protein member may also be used, in which case it is preferred that antibodies immunoreactive with other interacting protein members are also used in the assay.
  • nucleic acid probes may also be used in in situ hybridization assays to detect the localization or distribution of the mRNAs encoding the interacting protein members of a protein complex. Preferably, the mRNA encoding each interacting protein member of a protein complex is detected concurrently.
  • the method of diagnosis of the present invention comprises detecting any mutations in one or more interacting protein members of a protein complex of the present invention.
  • the kit can include one or more of the protein complexes of the present invention prepared or purified from a normal individual or an individual afflicted with a physiological disorder associated with an aberration in the protein complexes or an interacting protein member thereof.
  • the kit may further include one or more ofthe interacting protein members of the protein complexes of the present invention prepared or purified from a normal individual or an individual afflicted with a physiological disorder associated with an aberration in the protein complexes or an interacting protein member thereof.
  • random-sequence peptide phage display libraries may be generated by cloning synthetic oligonucleotides into the gene in or gene VIII of an E. coli. filamentous phage.
  • the thus generated phage can propagate in E. coli. and express peptides encoded by the oligonucleotides as fusion proteins on the surface of the phage. Scott and Smith, Science, 249:368-390 (1990).
  • the "peptides on plasmids" method may also be used to form peptide libraries.
  • random peptides may be fused to the C-terminus of the E. coli. Lac repressor by recombinant technologies and expressed from a plasmid that also contains Lac repressor-binding sites. As a result, the peptide fusions bind to the same plasmid that encodes them.
  • the chimeric genes encoding the fusion proteins of the present invention can be conveniently cloned into the expression vectors and placed under control of a viral promoter such as the 35S RNA and 19S RNA promoters of CaMV or the coat protein promoter of TMV, or of a plant promoter, e.g., the promoter of the small subunit of RUBISCO and heat shock promoters (e.g., soybean hspl7.5-E or hspl7.3-B promoters).
  • a viral promoter such as the 35S RNA and 19S RNA promoters of CaMV or the coat protein promoter of TMV
  • a plant promoter e.g., the promoter of the small subunit of RUBISCO and heat shock promoters (e.g., soybean hspl7.5-E or hspl7.3-B promoters).
  • the bait and prey vectors for recombinant expression in yeast include a yeast replication origin such as the 2i origin or the ARSH4 sequence for the replication and maintenance ofthe vectors in yeast cells.
  • the vectors also have a bacteria origin of replication (e.g., ColEl) and a bacteria selection marker (e.g., amp R marker, i.e., bla gene).
  • the CEN6 centromeric sequence is included to control the replication of the vectors in yeast cells.
  • Any constitutive or inducible promoters capable of driving gene transcription in yeast cells may be employed to control the expression of the chimeric genes. Such promoters are operably linked to the chimeric genes.
  • suitable constitutive promoters include but are not limited to the yeast ADH1, PGK1, TEF2, GPD1, HIS3, and CYC1 promoters.
  • suitable inducible promoters include bul are not limited to the yeast GALl (inducible by galactose), CUP1 (inducible by Cu ++ ), and FUS1 (inducible by pheromone) promoters; the AOX/MOX promoter from H. polymorpha and P. Pastoris (repressed by glucose or ethanol and induced by methanol); chimeric promoters such as those that contain LexA operators (inducible by LexA-containing transcription factors); and the like.
  • auxotrophic markers including, but not limited to, URA3, HIS3, TRP1, LEU2, LYS2, ADE2, and the like.
  • the yeast host cells transformed with bait vector and/or prey vector are cultured in a medium lacking a particular nutrient.
  • selectable markers are not based on auxofrophies, but rather on resistance or sensitivity to an antibiotic or other xenobiotic.
  • a reporter protein may be a fusion protein having an epitope tag fused to a protein.
  • epitope tags include sequences derived from, e.g., influenza virus hemagglutinin (HA), Simian Virus 5 (V5), polyhistidine (6xHis), c-myc, lacZ, GST, and the like. Antibodies specific to these epitope tags are generally commercially available.
  • the expressed reporter can be detected using an epitope-specific antibody in an immunoassay.
  • the reporter is selected such that it can be detected by a color-based assay.
  • yeast cells cannot convert non- toxic 5-fh ⁇ oroorolic acid (5-FOA) to a toxic product, 5-fluorouracil.
  • 5-FOA non- toxic 5-fh ⁇ oroorolic acid
  • yeast cells are resistant to 5-FOA and can grow on a medium containing 5-FOA. Therefore, for example, to screen for a compound capable of disrupting interaction between BTC and PROTEIN2, BTC can be expressed as a fusion protein with a DNA-binding domain of a suitable transcription activator while PROTEIN2 is expressed as a fusion protein with a transcription activation domain of a suitable transcription activator.
  • a protein complex identified in accordance with the present invention which comprises BTC and a member ofthe GROUPl.
  • methods are also provided for reducing in a patient the level and/or activity of a BTC- interacting protein selected from the GROUPl.
  • a nucleic acid encoding a desirable protein e.g., one selected from BTC, GROUPl is inco ⁇ orated into a suitable expression vector and is operably linked to a promoter in the vector.
  • viral vectors may also be used.
  • the viral genome is engineered to eliminate the disease-causing capability, e.g., the ability to replicate in the host cells.
  • the exogenous nucleic acid lo be introduced into a patient may be inco ⁇ orated into the engineered viral genome, e.g., by inserting it into a viral gene that is non-essential to the viral infectivity.
  • Viral vectors are convenient to use as they can be easily introduced into tissue cells by way of infection.
  • the recombinant virus typically is integrated into the genome of the host cell. In rare instances, the recombinant virus may also replicate and remain as extrachromosomal elements.
  • a cell model over-expressing one or more of the protein complexes of the present invention is provided.
  • the cell model may be established by increasing the expression level of one or more of the interacting protem members of the protein complexes.
  • all interacting protein members of a particular protein complex are over-expressed.
  • the over-expression may be achieved by introducing into host cells exogenous nucleic acids encoding the proteins to be over- expressed, and selecting those cells that over-express the proteins.
  • the expression of the exogenous nucleic acids may be transient or, preferably stable.
  • the recombinant expression methods described in Section 2.2, and the methods for introducing nucleic acids into host cells disclosed in the context of gene therapy in Section 6.2.2 may be used.
  • the transgenic animal of this invention exhibits aberrant interactions between BTC and a BTC-interacting protein selected from the group of GROUPl.
  • a BTC-interacting protein selected from the group of GROUPl.
  • variants of BTC and its interaction partners exhibiting altered protein-protein interaction properties and the nucleic acid variants encoding such variant proteins may be obtained by random or site-specific mutagenesis in combination with a protein-protein interaction assay system, particularly the yeast two-hybrid system described in Section 5.3.1.
  • variants of BTC and its interaction partners exhibiting increased or decreased or abolished binding affinity to each other may be identified and isolated.
  • the transgenic animal of the present invention may be made to express such protein variants by modifying the endogenous genes.
  • PEGylated proteins are currently being used in protein replacement therapies and for other therapeutic uses.
  • PEGylated interferon PEG-INTRON A ®
  • PEGylated adenosine deaminase ADAGEN ®
  • SCIDS severe combined immunodeficiency disease
  • PEGylated L-asparaginase ONCAPSPAR ®
  • ALL acute lymphoblastic leukemia
  • covalent linkage between the polymer and the active compound and or the polymer itself is hydrolytically degradable under physiological conditions.
  • Such conjugates known as "prodrugs" can readily release the active compound inside the body. Controlled release of an active compound can also be achieved by inco ⁇ orating the active ingredient into microcapsules, nanocapsules, or hydrogels generally known in the art.
  • the clones corresponding to scFv fragments that bind the BTC- PROTETN2 complex and also binds BTC and/or PROTEIN2 may be selected.
  • the scFv genes in the clones are diversified by mutagenesis methods such as oligonucleotide- directed mutagenesis, error-prone PCR (See Lin-Goerke et al, Biotechniques, 23:409 (1997)), dNTP analogues (See Zaccolo et al, J. Mol. Biol, 255:589 (1996)), and other methods.
  • the diversified clones are further screened in phage display or ribosome display libraries. In this manner, scFv fragments selectively immunoreactive with the BTC-PROTETN2 complex may be obtained.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Wood Science & Technology (AREA)
  • Microbiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Cell Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Endocrinology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Food Science & Technology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Toxicology (AREA)
  • Biophysics (AREA)
  • Peptides Or Proteins (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne des complexes protéiques contenant BTC et une ou plusieurs protéines sélectionnées dans le groupe constitué par GROUP1. Cette invention concerne également des méthodes d'utilisation de ces complexes protéiques dans le diagnostic de maladies et de troubles. En outre, lesdits complexes protéiques sont également utiles dans des méthodes de criblage permettant d'identifier des composés efficaces dans le traitement et/ou la prévention de maladies et de troubles associés à BTC et ses interacteurs.
PCT/JP2004/003699 2003-03-19 2004-03-18 Proteines interagissant avec btc et utilisation de ces proteines WO2004083241A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US45600703P 2003-03-19 2003-03-19
US60/456,007 2003-03-19
US45994403P 2003-04-02 2003-04-02
US60/459,944 2003-04-02

Publications (2)

Publication Number Publication Date
WO2004083241A2 true WO2004083241A2 (fr) 2004-09-30
WO2004083241A3 WO2004083241A3 (fr) 2005-03-31

Family

ID=33032708

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2004/003699 WO2004083241A2 (fr) 2003-03-19 2004-03-18 Proteines interagissant avec btc et utilisation de ces proteines

Country Status (1)

Country Link
WO (1) WO2004083241A2 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011041761A1 (fr) * 2009-10-02 2011-04-07 Blanchette Rockefeller Neurosciences Institute Profils de croissance de fibroblastes pour le diagnostic de la maladie d'alzheimer
US20140011689A1 (en) * 2003-11-19 2014-01-09 Ray Sandip Methods and compositions for diagnosis, stratification, and monitoring of alzheimer's disease and other neurological disorders in body fluids
WO2014039189A1 (fr) 2012-08-01 2014-03-13 Mcnally Elizabeth Réduction des lésions tissulaires et de la fibrose via la protéine-4 de liaison au tgf bêta latent (ltbp4)
US8822166B2 (en) 2008-07-28 2014-09-02 Blanchette Rockefeller Neurosciences Institute Stimulus-elicited genomic profile markers of alzheimer's disease
US9119825B2 (en) 2008-07-28 2015-09-01 Blanchette Rockefeller Neurosciences Institute PKC-activating compounds for the treatment of neurodegenerative diseases
US9163032B2 (en) 2011-11-13 2015-10-20 Blanchette Rockefeller Neurosciences Insitute Esters of DCPLA and methods of treatment using the same
US9188595B2 (en) 2001-02-27 2015-11-17 Blanchett Rockefeller Neurosciences Institute Alzheimer's disease diagnosis based on mitogen-activated protein kinase phosphorylation
US9797913B2 (en) 2005-10-11 2017-10-24 Blanchette Rockefeller Neuroscienses Inc. Alzheimer's disease-specific alterations of the ERK1/ERK2 phosphorylation ratio-alzheimer's disease-specific molecular biomarkers (ADSMB)
WO2022013787A1 (fr) 2020-07-16 2022-01-20 Novartis Ag Anticorps anti-bêtacelluline, fragments de ceux-ci et molécules de liaison multi-spécifiques
US11607443B2 (en) * 2016-12-22 2023-03-21 Universite Toulouse Iii-Paul Sabatier Therapeutic peptides

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BARTEL P L ET AL: "ANALYZING PROTEIN-PROTEIN INTERACTIONS USING TWO-HYBRID SYSTEM" METHODS IN ENZYMOLOGY, ACADEMIC PRESS INC, SAN DIEGO, CA, US, vol. 254, 1995, pages 241-263, XP001013374 ISSN: 0076-6879 *
DATABASE EMBL [Online] 1 June 2003 (2003-06-01), STRAUSBERG ET AL.: "Protein similar to prickle-like 1" XP002284782 Database accession no. Q80Y24 *
DUNBAR ANDREW J ET AL: "Structure-function and biological role of betacellulin" INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELL BIOLOGY, vol. 32, no. 8, August 2000 (2000-08), pages 805-815, XP002284781 ISSN: 1357-2725 *
KATOH MASUKO ET AL: "Identification and characterization of human PRICKLE1 and PRICKLE2 genes as well as mouse Prickle1 and Prickle2 genes homologous to Drosophila tissue polarity gene prickle." INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, vol. 11, no. 2, February 2003 (2003-02), pages 249-256, XP009032404 ISSN: 1107-3756 (ISSN print) *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9188595B2 (en) 2001-02-27 2015-11-17 Blanchett Rockefeller Neurosciences Institute Alzheimer's disease diagnosis based on mitogen-activated protein kinase phosphorylation
US20140011689A1 (en) * 2003-11-19 2014-01-09 Ray Sandip Methods and compositions for diagnosis, stratification, and monitoring of alzheimer's disease and other neurological disorders in body fluids
US9797913B2 (en) 2005-10-11 2017-10-24 Blanchette Rockefeller Neuroscienses Inc. Alzheimer's disease-specific alterations of the ERK1/ERK2 phosphorylation ratio-alzheimer's disease-specific molecular biomarkers (ADSMB)
US9119825B2 (en) 2008-07-28 2015-09-01 Blanchette Rockefeller Neurosciences Institute PKC-activating compounds for the treatment of neurodegenerative diseases
US11820745B2 (en) 2008-07-28 2023-11-21 Synaptogenix, Inc. PKC-activating compounds for the treatment of neurodegenerative diseases
US8822166B2 (en) 2008-07-28 2014-09-02 Blanchette Rockefeller Neurosciences Institute Stimulus-elicited genomic profile markers of alzheimer's disease
US10696644B2 (en) 2008-07-28 2020-06-30 Cognitive Research Enterprises, Inc. PKC-activating compounds for the treatment of neurodegenerative diseases
US11390596B2 (en) 2008-07-28 2022-07-19 Synaptogenix, Inc. PKC-activating compounds for the treatment of neurodegenerative diseases
US10323011B2 (en) 2008-07-28 2019-06-18 Cognitive Research Enterprises, Inc. PKC-activating compounds for the treatment of neurodegenerative diseases
US8658134B2 (en) 2009-10-02 2014-02-25 Blanchette Rockefeller Neurosciences Institute Fibroblast growth patterns for diagnosis of Alzheimer's disease
CN102741693A (zh) * 2009-10-02 2012-10-17 布朗歇特洛克菲勒神经科学研究所 诊断阿尔茨海默病的成纤维细胞生长模式
WO2011041761A1 (fr) * 2009-10-02 2011-04-07 Blanchette Rockefeller Neurosciences Institute Profils de croissance de fibroblastes pour le diagnostic de la maladie d'alzheimer
US9163032B2 (en) 2011-11-13 2015-10-20 Blanchette Rockefeller Neurosciences Insitute Esters of DCPLA and methods of treatment using the same
US9873739B2 (en) 2012-08-01 2018-01-23 Ikaika Therapeutics, Llc Mitigating tissue damage and fibrosis via latent transforming growth factor beta binding protein (LTBP4)
EP3711771A1 (fr) * 2012-08-01 2020-09-23 Ikaika Therapeutics, LLC Atténuation de lésions tissulaires et de la fibrose par l'intermédiaire de la protéine de liaison bêta (ltbp4) d'un facteur de croissance de transformation latente
AU2013313282B2 (en) * 2012-08-01 2018-02-01 Ikaika Therapeutics, Llc Mitigating tissue damage and fibrosis via latent transforming growth factor beta binding protein (LTBP4)
AU2021200783B2 (en) * 2012-08-01 2022-10-06 Ikaika Therapeutics, Llc Mitigating tissue damage and fibrosis via latent transforming growth factor beta binding protein (LTBP4)
WO2014039189A1 (fr) 2012-08-01 2014-03-13 Mcnally Elizabeth Réduction des lésions tissulaires et de la fibrose via la protéine-4 de liaison au tgf bêta latent (ltbp4)
US11607443B2 (en) * 2016-12-22 2023-03-21 Universite Toulouse Iii-Paul Sabatier Therapeutic peptides
WO2022013787A1 (fr) 2020-07-16 2022-01-20 Novartis Ag Anticorps anti-bêtacelluline, fragments de ceux-ci et molécules de liaison multi-spécifiques
US11524998B2 (en) 2020-07-16 2022-12-13 Novartis Ag Anti-betacellulin antibodies, fragments thereof, and multi-specific binding molecules

Also Published As

Publication number Publication date
WO2004083241A3 (fr) 2005-03-31

Similar Documents

Publication Publication Date Title
US20050222029A1 (en) Compositions and methods for treating diseases
US20020177692A1 (en) BCL-XL-interacting protein and use thereof
US20040226056A1 (en) Compositions and methods for treating neurological disorders and diseases
US20050112118A1 (en) Compositions and methods for treating inflammatory disorders
US20090087436A1 (en) Compositions and methods for treating diseases
US20070254300A1 (en) Compositions and methods for treating inflammatory disorders
US20020177207A1 (en) Tsg101-interacting proteins and use thereof
US20020197691A1 (en) FLT4-interacting proteins and use thereof
WO2011062962A2 (fr) Dégron smndelta7 : nouvelles compositions et procédés d'utilisation
WO2004083241A2 (fr) Proteines interagissant avec btc et utilisation de ces proteines
US7544475B2 (en) Depression gene
EP2275547B1 (fr) Polynucléotides et séquences de polypeptide impliquées dans le procédé de remodelage des os
US20030008373A1 (en) APOA1-interacting proteins and use thereof
US20090035853A1 (en) Tsg101-gag interaction and use thereof
US20020173026A1 (en) Survivin-interacting proteins and use thereof
JP2003510078A (ja) Ｍａｃａｃａｆａｓｃｉｃｕｌａｒｉｓ由来のＰ−糖タンパク質およびその使用
EP1377165B1 (fr) Interaction tsg101-gag et son utilisation
WO1998056806A1 (fr) Proteine de coactivation de facteur de transcription, p/cip
US7297515B1 (en) Zinc finger proteins
AU3879700A (en) Hermansky pudlak syndrome protein-interacting proteins and methods of use thereof
US20030036163A1 (en) Novel PN9826 nucleic acids and use thereof
US6831154B1 (en) Membrane-associated protein 17KD (MAP17)-interacting protein and use thereof
US20050100966A1 (en) FHOS-interacting proteins and use thereof
US6828421B1 (en) VAMP-associated protein A-interacting proteins and use thereof
US20030022330A1 (en) APOA2-interacting proteins and use thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase