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Creating Mouse Models to Study the Link Betwee PTPN22 and ACPA+ RA

创建小鼠模型来研究 PTPN22 和 ACPA RA 之间的联系

基本信息

批准号：
9300832
负责人：
LINDA A SHERMAN
金额：
$ 21.18万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-17 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9300832
关键词：
Address Affect Affinity Alleles Amino Acids Animals Antigens Arginine Arthritis Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Automobile Driving B-Lymphocytes Binding Biochemical Pathway Biopsy Specimen C-terminal CD4 Positive T Lymphocytes CRISPR/Cas technology Cells Charge Chronic Citrulline Collaborations Disease Disease susceptibility Enzymes Epitopes Etiology Fibrinogen Generations Genetic Genetic Polymorphism Goals HLA-DRB1 Helper-Inducer T-Lymphocyte Hematopoietic Homeostasis Human Hydrolysis Immune Immune response Immunize Inflammatory Knockout Mice Knowledge Link Mediating Modeling Molecular Mus Mutation PTPN22 gene Pain Pathogenesis Pathway interactions Patients Peptide antibodies Peptides Phenotype Plasma Population Post-Translational Protein Processing Predisposition Protein Tyrosine Phosphatase Protein-arginine deiminase Proteins Research Research Project Grants Rheumatoid Arthritis Role Single Nucleotide Polymorphism Susceptibility Gene Symptoms Synovial joint T cell response T-Lymphocyte TNFRSF10A gene Technology Testing Therapeutic Intervention Transgenic Mice Tryptophan Ursidae Family citrullinated protein disease phenotype genetic association genetic risk factor high risk innovation insight interest mouse model new therapeutic target proline-rich proteins public health relevance response scaffold systemic autoimmune disease

项目摘要

DESCRIPTION (provided by applicant): Rheumatoid Arthritis (RA) is a chronic inflammatory autoimmune disease that affects ~1% of the world population. Plasma and synovial biopsy specimen from patients with rheumatoid arthritis (RA) contain high levels of proteins containing the posttranslational modification citrulline. RA patients often develop autoimmune reactivity to citrullinated proteins. In fact, the formation of anti-citrulline peptide antibodies (ACPAs) is higly specific to RA, and their presence correlates with the most erosive form of disease. There is a strong association between the presence of ACPAs and the RA susceptibility HLA-DRB1, so called "shared epitope" alleles, because the SE alleles bind citrulline-containing peptides with high affinity, supporting a role for citrulline-specific T helper cells in driving the ACPA respons. Transgenic mice carrying the HLA-DRB1*04:01 SE allele (DR4-IE tg mice) develop a T cell and a B cell autoimmune response to citrullinated but not uncitrullinated fibrinogen; however, only ~35% of immunized DR4-IE tg animals developed arthritic disease, which has limited the general utility of this model. Of the non-HLA susceptibility genes, the PTPN22 single nucleotide polymorphism of 1858C>T has the highest genetic association with RA. PTPN22 is a tyrosine phosphatase expressed in hematopoietic cells that regulates immune homeostasis and activation. The PTPN22 polymorphism results in the mutation of arginine 620 to a tryptophan residue (R620W) within a C-terminal proline-rich protein interaction domain. The PTPN22 1858C>T polymorphism bears a much stronger association with ACPA+ than with ACPA- RA. Therefore, we hypothesize that a functional PTPN22 allele restrains the arthritic disease phenotype in DR4-IE tg mice that have been immunized with citrullinated fibrinogen. To test our hypothesis, we have introduced perturbations of the murine PTPN22 gene onto the DR4-IE tg line, with the goal to model the human RA condition. These lines will be immunized with citrullinated fibrinogen to induce anti-citrulline driven arthritis. We have already crossed PTPN22 KO mice onto the DR4-IE tg background. Additionally, we have generated mice bearing a mutation in the PTPN22 locus that is equivalent to the human R620W polymorphism (R619W) using CRISPR/Cas 9 technology, a strategy we have also successfully used to generate PTPN22 R619W mice on the NOD background. Since deletion of PTPN22 and the R619W mutation do not lead to entirely equivalent phenotypes, finely dissecting the role of PTPN22 on anti-citrulline driven arthritis will require both mouse lines. This is an innovative, high-risk/hih gain proposal because 1) it aims to create a robust arthritis model that is driven by citrullinated antigens and 2) these studies will be critical for understanding the etiology of RA, especially ACPA+ RA. .