Tools to evaluate POP2 as a regulator of arthritis

评估 POP2 作为关节炎调节剂的工具

• 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
• 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

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.

项目概要： 炎症是类风湿性关节炎（RA）的致残表现和并发症的基础。遗传 个体之间炎症信号调节的差异是高度相关和重要的， 这种差异可能决定了哪些个体会发展为RA，他们疾病的严重程度， 甚至会影响姑息治疗的选择。我们对病理生理学的理解 部分基于动物模型。然而，最近的研究表明， 编码限制NF-κ B信号传导的仅Pyrin和仅CARD蛋白（POP和COP）的基因， 炎症小体激活途径，对于介导炎症的细胞因子的加工至关重要的事件。我们 已经确定了POP 2的一个等位基因与严重的，可能是治疗抵抗性RA相关。评价 这种RA相关等位基因在体内和体外的功能将有助于揭示RA的免疫学和分子基础， 为协会，并提供深入了解为什么一些RA患者发展严重的RA耐药，否则 有效的治疗与先进的生物制剂靶向TNF和IL-6。这些知识可以帮助指导 临床决策和推进努力，以确定新的治疗方式。本申请提出 转基因小鼠模型和细胞工具，以研究与RA相关的POP 2等位基因的性质。 这些工具是进一步研究POP 2在RA疾病中的功能的必要的第一步。