Tools to evaluate POP2 as a regulator of arthritis

项目总结： 炎症是类风湿性关节炎(RA)致残性表现和共病的基础。遗传 个体之间炎症信号调节的差异具有高度相关性和重要意义 这些差异可能决定了那些将发展为RA的人，他们的疾病的严重程度，以及 甚至会影响治标不治本的治疗方案。我们对病理生理学的大部分理解 RA的研究在一定程度上是基于动物模型。然而，最近的研究表明，人类拥有七个 编码纯吡喃和纯卡片蛋白(POPS和COPS)的基因限制了NF-kB信号和 炎症体激活途径，对于阐述介导炎症的细胞因子至关重要的事件。我们 已经确定了POP2的一个等位基因与严重的和可能的治疗耐药的RA相关。评估 这种RA相关等位基因在体内和体外的功能将有助于揭示其免疫学和分子基础 并洞察为什么一些RA患者会对其他疗法产生严重的RA抵抗 使用针对肿瘤坏死因子和白介素6的复杂生物制剂进行有效治疗。这样的知识可以帮助指导 临床决策和推进努力，以确定新的治疗方式。此应用程序建议 一种转基因小鼠模型和细胞工具，用于研究与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的第一步。

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.