CN110031637A - It is a kind of to be tracked and the kit of monitoring and its application for treating ankylosing spondylitis - Google Patents
It is a kind of to be tracked and the kit of monitoring and its application for treating ankylosing spondylitis Download PDFInfo
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- CN110031637A CN110031637A CN201910440479.3A CN201910440479A CN110031637A CN 110031637 A CN110031637 A CN 110031637A CN 201910440479 A CN201910440479 A CN 201910440479A CN 110031637 A CN110031637 A CN 110031637A
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- 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
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Abstract
A kind of kit and its application for treating ankylosing spondylitis tracking with monitoring, belongs to technical field of biomedical materials.To find the marker with a new, more accurate early diagnosis, treatment tracking, the present invention provides a kind of the following technical solution: a histone marker tracks the application with monitoring in treating ankylosing spondylitis, and the protein marker includes SAA1, IRF6, RBP4, ROR2, osteocalcin, PDGFR- β and/or ADAMTS-10.The beneficial effects of the present invention are: (1) present invention selected by marker all have preferable sensibility and specificity.(2) marker selected by the present invention is protein, can be detected by a variety of methods, related with therapeutic response, is convenient for clinical application.(3) this research institute sortilin matter can achieve better sensibility and specificity in the case where joint-detection.
Description
Technical field
The present invention relates to ankylosing spondylitis protein markers, more particularly to a kind of ankylosing spondylitis biology
Marker, a kind of side being early diagnosed, treated tracking to ankylosing spondylitis using ankylosing spondylitis biomarker
Method belongs to technical field of biomedical materials.
Background technique
Ankylosing spondylitis, which is that one kind is main, to be invaded backbone and involves skeletal joint and periarticular, can be with uvea
The chronic inflammation disease of symptom outside the joints such as scorching, inflammatory enteritis and psoriasis.Mostly between twenty and fifty onset, male is common, early
Phase often shows as middle axis joint and periphery affected joints pain, morning stiffness, deuterogenesis's bony ankylosis.Ankylosing spondylitis disease so far
Because not yet clear, research thinks that its morbidity is mainly determined by inheritance susceptible factor, and environmental factor such as smokes, infects and send out in disease
It also plays an important role in raw, generating process.Onset concealment, early symptom is lighter, and symptom cannot be sent out in early days mostly without specificity
It is existing, it is one of the disease of Delay in Diagnosis most serious in rheumatic disease, finally clarifying a diagnosis to disease occurs from initial symptom,
AS will often continue averagely to need 5-10.Early diagnosis, early treatment is the key that prevent disease progression, prevent deformity.With
The application of tumor necrosis factor (Tumor Necrosis Factor, TNF) inhibitor, the therapeutic effect of ankylosing spondylitis
Greatly improve, however it is not all meet all receive the treatment of TNF- alpha inhibitor using the patient of indication and obtain the phase
To effect.The common protein markers clinically for ankylosing spondylitis diagnosis, treatment tracking are erythrocyte sedimentation rate at present
(ESR), two inflammation indexes of C reactive protein (CRP).However ESR and CRP are very common diseases in clinical practice and test
Sick mobility marker, susceptibility and specificity are all lower, and cannot reflect the disease process of ankylosing spondylitis comprehensively.This
Outside, only the CRP or ESR level of 40-50% patients with ankylosing spondylitis be it is raised, ESR or CRP level can not normally exclude
AS active state.Other than CRP, ESR, has multinomial research and report life related with ankylosing spondylitis disease activity
Object marker, such as IL-6, IL-17, MMP3, OPG, but that there are clinical detections is difficult, unrelated with therapeutic response for these markers
The defects of.In addition ankylosing spondylitis is the complex disease of a multifactor participation, and single marker detection may not necessarily be anti-very well
Disease treatment situation is reflected, therefore, needs to find the new marker that can be used for early diagnosing, treat tracking.
Summary of the invention
Mentioned above to solve the problems, such as, the present invention provides a kind of the following technical solution:
One histone marker tracks the application with monitoring in treating ankylosing spondylitis, and the protein marker includes
There are SAA1, IRF6, RBP4, ROR2, osteocalcin, PDGFR- β and/or ADAMTS-10.
Human serum amyloid protein (serum amyloid A, SAA) belongs to the heterogeneous albuminoid in apolipoprotein family
Matter is made of tetra- members of SAA1, SAA2, SAA3 and SAA4, previously research confirm family wherein SAA1 be it is main composition at
Point, expressed in family most extensively, activity is most strong, reaction is most sensitive.The protein is main acute phase protein, response
In inflammation and tissue damage, height is expressed.High-caliber this protein is related with chronic inflammatory disease, including artery is athero-
Hardening, rheumatoid arthritis, Alzheimer disease and Crohn disease.
Interferon regulatory factor (interferon regulatory factor, IRF) family is that a major class plays IFN
The transcription factor of regulating and controlling effect.IRF family includes 10 members, and family member shares highly conserved N- terminal helix-and turns
Angle-helical dna binding structural domain and less conservative C- terminal protein binding structural domain.Although IRF6 in structure with IRF family
Other members of race are similar, but the function for it in the innate immunity is known little about it at present.Mainly collect about the research of work at present
In in terms of the mature differentiation of regulation epithelial cell, IRF6 is high in skin keratinocytes to express, and in keratinocyte differentiation
It is played a key role in mature process.The mutation of IRF6 gene can cause van der Woude syndrome and rouge wing descendants
Meat syndrome is also related to the oral jaw facial cleft type 6 of non-syndrome.Temporarily without research shows that IRF6 and ankylosing spondylitis hair
It is sick related.
Retinol-binding proteins (retinol-binding protein 4, RBP4) belong to lipocalin protein family,
It is the idiosyncratic carrier of retinol in blood (retinol).Retinol is stored into peripheral tissues from liver by it.In blood plasma
In, RBP- retinoyl complex and transthyretin interact, and prevent its transfer by glomerular filtration.Lack dimension life
Plain A blocks protein-bonded secretion upon translation and leads to the delivering and supply defect to epidermal cell.Its serum levels is often made
For clinical nutrition situation, the evaluation index of the early diagnosis of liver and kidney disease and curative effect.RBP ELISA is a kind of new rouge
Fat source property courier, takes part in the generation of insulin resistance and patients with type Ⅰ DM.
Receptor tyrosine kinase sample orphan receptor (tyrosine-protein kinase transmembrane
Receptor, ROR2), which is receptor protein tyrosine kinase and I type transmembrane protein, belongs to cell surface receptor
ROR subfamily.Protein may participate in the early formation of cartilage cell, and may be that cartilage and growth plate development institute are required
's.The mutation of the gene can cause short finger-type Type B, this be it is a kind of with distal phalanx and onychodysostosis/hypoplasia for spy
The skeletal diseases of sign.In addition, the mutation of the gene can cause the autosomal recessive form of Robinow syndrome, feature exists
It is bad with systemic bones of extremities cripetura, spinal segments defect, short finger-like, and the facial appearance of deformation in skeleton development.Both
Toward the correlation without research report ROR2 and ankylosing spondylitis.
Osteocalcin (osteocalcin), also known as BoneGlaprotein (bone Gla protein, BGLAP), are by skeletonization
The height bone protein abundant of cell secretion, adjusts bone remodeling and energetic supersession.The protein contains Gla (γ carboxyl paddy ammonia
Acid) structural domain, works in conjunction with calcium and hydroxyapatite (mineralogical composition of bone).Research thinks that osteocalcin's is main
Function is to maintain the normal mineralization rate of bone, inhibits the formation of abnormal light base apatite, inhibits the speed of growth cartilage mineralization, with
Bone mineralising occurs simultaneously, and increases with bone growth, light apatite deposition.The mouse of gene knockout shows as bon e formation and bone
Amount increases, and bone resorption and bone mineralising are not affected, and prompt may inhibit osteoblast activity.It is previously a small number of related
The contradiction of osteocalcin and ankylosing spondylitis report.
Platelet derived growth factor receptor-β (platelet-derived growth factor receptor
Beta, PDGFR- β) be platelet derived growth factor family member cell surface tyrosine kinase receptor.It is platelet-derived
Growth factor is the homotype being formed by connecting by two polypeptide chains by disulfide bond or heterodimer, when tissue is damaged by
Macrophage, monocyte, vascular smooth muscle cells, fibroblast, endothelial cell etc. can be synthesized and be discharged.PDGFR-β
Normal development for cardiovascular system is required, and facilitates the rearrangement of actin cytoskeleton.Encode the albumen
Gene is located at granulocyte-macrophage colony stimutaing factor and macrophage colony-stimulating factor receptor on No. 5 chromosomes
Gene side；All these three genes all may be related with 5-q syndrome.Transposition between chromosome 5 and 12 make the gene with
ETV6 Gene Fusion leads to the chronic myeloproliferative disease of eosinophilia.There are not PDGFR- β and tatanic ridge
The relevant report of column inflammation.
Adam protein (a disintegrin and of the thrombospondin of type containing I
Metalloproteinase with thrombospondin motifs, ADAMTS) it is zinc dependence protein enzyme family.
ADAMTS protease is compound secretase, contains the preceding protease structure for being attached to the plain type of repetition dissolution of auxiliary domains
Domain, with highly conserved structure comprising at least one platelet factor4 type repeats.Family is one kind a variety of
The protease family that adjustment effect is played in disease, participates in a variety of human physiological's property and pathologic physiological processes, is demonstrate,proved
It is bright in connective tissue tissue, blood coagulation, inflammation, arthritis plays a significant role in angiogenesis and cell migration, in growth and skin
It plays a major role in skin, crystalline lens and heart development.The gene for encoding ADAMTS-10 is autosomal recessive Weill-
The candidate gene of Marchesani syndrome, the gene mutation can seriously affect the structure and function of microfibril, promote
It is deposited in fibroblastic extracellular matrix that fibrillin-1 is cultivated in vitro.ADMATS-1O is previously in rigid spine
Without report in inflammation.
The present invention also provides a kind of kit tracked for treating ankylosing spondylitis with monitoring, the kit is used
SAA1, IRF6, RBP4, ROR2, osteocalcin, PDGFR- β and/or ADAMTS- in subject's body fluid, cell and/or tissue
The corresponding antibody of expression quantity, and/or protein label, and/or protein label of 10 protein labels are corresponding
The qPCR primer and/or probe of mRNA is detected.
Further, the body fluid and tissue includes peripheral blood, serum, blood plasma, knuckle synovia, urine, tear, peripheral blood
Mononuclearcell, lymphocyte, osteoblast, osteoclast, mescenchymal stem cell, ligament tissue, tendon tissue, bone tissue,
Musculature and/or adipose tissue.
Further, the detection method that kit uses is miniflow hole, illumina, chemoluminescence method, ELISA, fluorescence
Quantitative PCR, chip or paramagnetic particle method, micro-fluidic chip, chemoluminescence method, ELISA, quantitative fluorescent PCR.
The present invention provides a kind for the treatment of albumen marker in the drug of ankylosing spondylitis again, and the drug is for lowering
The expression of patient's body SAA1 and/or IRF6, or up-regulation ADAMTS-10, ROR2, PDGFR- β, RBP4 and/or
The expression of Osteocalcin.
The beneficial effects of the present invention are:
(1) marker selected by the present invention all has preferable sensibility and specificity.
(2) marker selected by the present invention is protein, can be detected by a variety of methods, related with therapeutic response, convenient for facing
Bed application.
(3) this research institute sortilin matter can achieve better sensibility and specificity in the case where joint-detection.
Detailed description of the invention
Fig. 1 is 7 marker expression schematic diagrames in AS patient；
Fig. 2 is the ROC curve that 7 protein buildings judge individual state.
Specific embodiment
(1) sample collection and extraction
Patients with ankylosing spondylitis is all from The Third Affiliated Hospital of Zhongshan University, acquires the whole blood of AS patient and normal control
Sample is placed at room temperature for 3000g in hour and is centrifuged 5 minutes, and Aspirate supernatant is transferred to sterile EP tube, saves after packing in -80 DEG C
To detection.
(2) experimental material and reagent
1) AAH-BLG-1000 kit, kit include content:
Slide chip, labelled reagent, terminate liquid, Block buffer, label buffer, 1500 × fluorescent marker strepto- is affine
The washing lotion II of washing lotion I, 20X of element, dialysis tubing and buoy, 20X.
2) material and instrument needed in addition to kit:
Plastic centrifuge tube (0.5-4mL, 50mL), 1X PBS (pH=8.0), shaking table, plastic fresh-keeping membrane, double distilled water,
InnoScan 300Microarray Scanner Fluorescence Scanner, Thermo Scientific Wellwash Versa chip
Board-washing machine.
(3) experimental procedure
1) sample is dialysed
1. pipette samples are dialysed (Item A).
It dialyses while stirring for 4 DEG C 2. dialysis tubing is placed in 1 × PBS (pH=8) of 4000mL.It is saturating to be spaced replacement in 3 hours
It is primary to analyse liquid, protein concentration is measured after dialysis.
3. determination of protein concentration and dilution scheme.
It needs to measure protein concentration after dialysis, protein concentration is detected using BCA kit.
2) biotin labeling sample
1. after labelled reagent tubule rapid centrifugation, 100 1 × PBS of μ L dissolution is added into pipe using before labelled reagent
Powder, piping and druming mixes labelled reagent up and down, is prepared into 1 × labelled reagent solution (1X Labeling Reagent).
2. the sample and labelled reagent of appropriate amount are added into new centrifuge tube.It quickly mixes, is incubated at room temperature on shaking table
30min, every 5min flick centrifuge tube, hybrid reaction reagent.
3. 3 μ L terminate liquids are added in upper step reaction solution.
4. separately sampled product 200ul is added in dialysis tubing, then 4 DEG C of side stirrings in 1 × PBS of 4000mL (pH=8)
Side dialysis, it is primary to be spaced 3 hours replacement dialyzates, collection sample after dialysis three times.
3) slide chip is completely dried
Slide chip is taken out from box, after equilibrium at room temperature 1h, packaging bag is opened, opens sealing strip, then
Chip is placed on the dry 1h of vacuum desiccator.
4) it closes and is incubated for
1. 1 × confining liquid of 400 μ L is added in each chip hole, it is incubated for 1h on room temperature shaker, avoids generating bubble.
2. pumping confining liquid, 400 μ L samples, one sample of an array are added in every hole, 4 DEG C of shaken overnights are incubated for.
3. sample dilutes 300 times of loadings with confining liquid.
4. pumping sample, 1 × washing lotion I (20 × washing lotion is diluted with deionized water) room temperature vibration of about 1mL is added in each hole
It swings, washes slide 4 times, each 5min.
5. pumping 1 × washing lotion I, 1 × washing lotion II shaken at room temperature is added, washes slide 4 times, each 5min.
6. pumping 1 × washing lotion II, the confining liquid of 1ml, then 5 times of dilutions are added in Cy3equivalent.400 μ L are added in every hole
Room temperature is protected from light oscillation incubation 2 hours.
7. 4. and 5. washing slide according to step.
5) fluorescence detection
1. laser scanner such as 300 scanning signal of InnoScan is used, using Cy3 or green channel (stimulating frequency
=532nm).
2. extracting data using chip analysis software, data are carried out using the Data Analysis Software of (AAH-BLG-1000)
Analysis.
(3) data are analyzed
Total data (signal strength) is uniformed after removal background, while significant using software progress group difference
Property analysis, difference is gone out according to p < 0.05 and Fold change (AS patient/normal healthy controls) > 1.5 or 1/1.5 standard screening of <
Protein.In patients with ankylosing spondylitis is compared with normal healthy controls, 33 protein express raising (packet in AS patient
Include SAA1, IRF6), 20 protein expressed in AS patient reduction (including ADAMTS-10, ROR2, RBP4,
Osteocalcin,PDGFR-β)；In patients with ankylosing spondylitis, after TNF-α antagonist for treating, 32 protein expressions
Raise (including ADAMTS-10, ROR2, RBP4, Osteocalcin, PDGFR- β), 10 protein expressions lower (including
SAA1, IRF6), as shown in Figure 1.
(4) selection of candidate protein markers object
Based on above-mentioned two groups of comparison in difference as a result, in AS patient and normal healthy controls differential expression 7 protein, pass through
Occur significantly to sexually revise after TNF-α antagonist for treating.Wherein SAA1, IRF6 express raising in AS patient, through TNF-α antagonist
It expresses and lowers after treatment；ADAMTS-10, ROR2, RBP4, Osteocalcin, PDGFR- β express decline in AS, through TNF-α
Up-regulation is expressed after antagonist for treating.Judge that the ROC curve of individual state, AUC reach using the building of above 7 protein
0.990.Therefore the method that 7 kinds of protein of the present invention can provide early stage non-invasive diagnostic ankylosing spondylitis morbid state
And biomarker, and can be applied to treating ankylosing spondylitis tracking and monitoring.
Claims (5)
1. a histone marker tracks the application with monitoring in treating ankylosing spondylitis, which is characterized in that the albumen
Marker includes SAA1, IRF6, RBP4, ROR2, osteocalcin, PDGFR- β and/or ADAMTS-10.
2. a kind of kit tracked for treating ankylosing spondylitis with monitoring, which is characterized in that the kit is used for
To subject's body fluid, cell and/or organize interior SAA1, IRF6, RBP4, ROR2, osteocalcin, PDGFR- β and/or ADAMTS-10
The corresponding antibody of expression quantity, and/or protein label, and/or the corresponding mRNA of protein label of protein label
QPCR primer and/or probe detected.
3. a kind of kit tracked for treating ankylosing spondylitis with monitoring as claimed in claim 2, which is characterized in that
The body fluid and tissue includes that peripheral blood, serum, blood plasma, knuckle synovia, urine, tear, peripheral blood mononuclear cells, lymph are thin
Born of the same parents, osteoblast, osteoclast, mescenchymal stem cell, ligament tissue, tendon tissue, bone tissue, musculature and/or fat
Tissue.
4. a kind of kit tracked for treating ankylosing spondylitis with monitoring as claimed in claim 2, which is characterized in that
The detection method that kit uses is micro-fluidic chip, chemoluminescence method, ELISA, quantitative fluorescent PCR.
5. a kind for the treatment of albumen marker is in the drug of ankylosing spondylitis, which is characterized in that the drug is suffered from for lowering
The expression of SAA1 and/or IRF6 in person's body, or up-regulation ADAMTS-10, ROR2, PDGFR- β, RBP4 and/or
The expression of Osteocalcin.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111748615A (en) * | 2020-05-14 | 2020-10-09 | 南京医科大学附属逸夫医院 | Detection method of RBP4 as sarcopenia treatment target |
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| CN101452001A (en) * | 2007-12-06 | 2009-06-10 | 王颖 | Quantitative determination RBP4 kit by chemiluminescence magnetic enzymoimmune method |
| US20090227533A1 (en) * | 2007-06-08 | 2009-09-10 | Bader Andreas G | miR-34 Regulated Genes and Pathways as Targets for Therapeutic Intervention |
| US20100227317A1 (en) * | 2006-02-15 | 2010-09-09 | Timothy Thomson Okatsu | Method for the Molecular Diagnosis of Prostate Cancer and Kit for Implementing Same |
| CN103018358A (en) * | 2012-11-18 | 2013-04-03 | 浙江大学 | Kit for detecting pulmonary tuberculosis syndrome characteristic protein and application thereof |
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| US20100227317A1 (en) * | 2006-02-15 | 2010-09-09 | Timothy Thomson Okatsu | Method for the Molecular Diagnosis of Prostate Cancer and Kit for Implementing Same |
| US20090227533A1 (en) * | 2007-06-08 | 2009-09-10 | Bader Andreas G | miR-34 Regulated Genes and Pathways as Targets for Therapeutic Intervention |
| CN101173278A (en) * | 2007-10-22 | 2008-05-07 | 古洁若 | Ankylosing spondylitis pathopoiesia correlation gene IRS-1 mutant gene, detecting method and reagent kit thereof |
| CN101452001A (en) * | 2007-12-06 | 2009-06-10 | 王颖 | Quantitative determination RBP4 kit by chemiluminescence magnetic enzymoimmune method |
| CN103018358A (en) * | 2012-11-18 | 2013-04-03 | 浙江大学 | Kit for detecting pulmonary tuberculosis syndrome characteristic protein and application thereof |
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| CN111748615A (en) * | 2020-05-14 | 2020-10-09 | 南京医科大学附属逸夫医院 | Detection method of RBP4 as sarcopenia treatment target |
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