Tools to evaluate POP2 as a regulator of arthritis

评估 POP2 作为关节炎调节剂的工具

基本信息

批准号：
9979151
负责人：
JONATHAN A HARTON
金额：
$ 8.13万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979151
关键词：
Affect Alleles Animal Model Animals Arthritis Atherosclerosis Autoimmune Diseases Biological Biological Markers Biological Response Modifier Therapy Cartilage Cell Line Cells Chromosome 3 Chronic Code Collagen Arthritis Complement Development Disease Disease Resistance Engineering Evaluation Event Functional disorder Genes Genetic HLA-DRB1 Half-Life Human Immunologics Impairment In Vitro Incidence Individual Inflammasome Inflammation Inflammatory Interleukin-1 beta Interleukin-6 Investigation Joints Knowledge Laboratories Laboratory Animals Longevity Mediating Metabolic Diseases Modality Modeling Molecular Morbidity - disease rate Mouse Cell Line Mus NF-kappa B Nature Non-Insulin-Dependent Diabetes Mellitus Nucleic Acid Regulatory Sequences PTPN22 gene Pathogenesis Pathway interactions Patients Pattern Population Primates Proteins Quality of life Reagent Regulation Regulatory Element Resistance Rheumatoid Arthritis Risk Role Severities Severity of illness Signal Transduction System TNF gene Transgenes Transgenic Mice Transgenic Organisms United States Variant Work arthropathies base bone erosion clinical decision-making comorbidity cytokine economic cost effective therapy genetic variant in vivo inducible gene expression insight joint inflammation loss of function mRNA Expression macrophage marenostrin mouse model novel novel therapeutics palliative preservation success tool

项目摘要

Project Summary: Inflammation underlies the disabling manifestations and co-morbidities of rheumatoid arthritis (RA). Genetic differences in the regulation of inflammatory signaling between individuals are highly relevant and significant as such differences likely determine those individuals that will progress to RA, the severity of their disease, and even influence the treatment options that will be palliative. Much of our understanding of the pathophysiology of RA is based in part on animal models. However, recent work demonstrates that humans posses seven genes coding Pyrin-only and CARD-only proteins (POPs and COPs) that limit NF-kB signaling and infammasome activation pathways, events critical for elaboration of the cytokines mediating inflammation. We have identified an allele of POP2 associated with severe, and likely treatment resistant RA. Evaluating the function of this RA-associated allele in vivo and in vitro will help reveal the immunological and molecular basis for the association and provide insight into why some RA patients develop severe RA resistant to otherwise effective treatment with sophisticated biologics targeting TNF and IL-6. Such knowledge could help guide clinical decision making and advance efforts to identify new therapeutic modalities. This application proposes a transgenic mouse model and cellular tools to investigate the nature of the POP2 allele associated with RA. These tools are a necessary first step towards further investigation of the function of POP2 in RA disease.

项目摘要：炎症是类风湿关节炎（RA）的残疾表现和合并症的基础。遗传个体之间炎症信号传导调节的差异是高度相关和显着的，因为这种差异可能决定了那些将会发展为RA的人，其疾病的严重程度以及甚至会影响姑息治疗方案。我们对病理生理学的大部分理解 RA的部分基于动物模型。但是，最近的工作表明人类拥有七个限制NF-kb信号和的基因编码仅吡啶和仅卡的蛋白质（POP和COPS） Infampasome激活途径，对介导炎症的细胞因子阐述至关重要的事件。我们已经确定了与严重且可能具有耐药性RA相关的POP2等位基因。评估该RA相关等位基因在体内和体外的功能将有助于揭示免疫学和分子基础对于协会，并提供了有关某些RA患者为何会产生严重抗性的洞察力的见解针对TNF和IL-6的精致生物制剂的有效治疗。这样的知识可以帮助指导临床决策和提出努力以识别新的治疗方式。此申请提出转基因小鼠模型和细胞工具，以研究与RA相关的POP2等位基因的性质。这些工具是进一步研究POP2在RA疾病中的功能的必要第一步。