POP2 as a novel therapeutic in rheumatoid arthritis

项目摘要： 炎症是类风湿性关节炎（RA）的致残表现和并发症的基础。治疗 RA患者的治疗方案旨在控制炎症和由炎症介导的进行性关节损伤， 细胞因子包括TNFα、IL-1β和IL-6。最近的研究表明人类拥有四种基因 编码限制NF-κ B B信号传导和炎性体活化途径的仅限芘蛋白（POP）， 这对于介导炎症的细胞因子的加工至关重要。TNF、IL-1β和IL-6受以下因素的严重调节： NF-κ B B转录因子。我们之前已经描述了POP 2在体外的抗炎特性 和体内。在这里，我们提出了概念验证研究，以评估如何POP 2和POP 2衍生肽 使用小鼠临床前模型，当外源性给药时，影响实验诱导的RA。POP2 肽疗法代表了一种新的治疗方法， 抑制NF-κ B B信号传导和炎性体途径。免疫学和分子基础 我们的假设源于我们发表的初步数据，这些数据表明， POP 2肽抑制炎症反应中的细胞因子产生，而不损害宿主免疫力。 我们的研究将提供如何利用基于POP 2肽疗法的治疗方案的见解， 改进了。体外表征、剂量递增研究和疾病的体内评估 这些参数将为开发POP 2肽作为新型治疗剂提供信息。

Project Summary: Inflammation underlies the disabling manifestations and co-morbidities of rheumatoid arthritis (RA). Treatment regimens for RA patients aim to control inflammation and progressive joint damage mediated by inflammatory cytokines including TNFα, IL-1β, and IL-6. Recent studies demonstrate that humans possess four genes coding Pyrin-only proteins (POPs) that limit NF-B signaling and inflammasome activation pathways, events critical for elaboration of the cytokines mediating inflammation. TNF, IL-1β, and IL-6 are critically regulated by NF-B transcription factors. We have previously described the anti-inflammatory properties of POP2 in-vitro and in-vivo. Here we propose proof-of-concept studies to evaluate how POP2 and POP2-derived peptides impact experimentally induced RA when administered exogenously, using a murine preclinical model. POP2 peptide therapy represents a novel therapeutic approach to ameliorating excessive inflammation through dual inhibition of both NF-B signaling and inflammasome pathways. The immunological and molecular basis for our hypotheses stems from our published and preliminary data showing the naturally expressed, non-toxic POP2 peptide dampens cytokine production in inflammatory responses without compromising host immunity. Our studies will provide insight into how treatment regimens based on POP2 peptide therapy may be utilized or improved upon. In vitro characterization, dose-escalation studies and in-vivo assessment of disease parameters will inform approaches to develop POP2 peptides as a novel therapeutic.