POP2 as a novel therapeutic in rheumatoid 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。治疗 RA患者的治疗方案旨在控制炎症和炎症介导的进行性关节损害 细胞因子包括肿瘤坏死因子α、白介素1β和白介素6。最近的研究表明，人类拥有四个基因 编码限制NF-B信号和炎性小体激活途径和事件的仅吡咯蛋白(POP) 对于阐述介导炎症的细胞因子至关重要。肿瘤坏死因子、白介素1β和白介素6受 核因子-B转录因子。我们之前已经描述了POP2的体外抗炎特性 和活体内。在这里，我们提出了概念验证研究来评估POP2和POP2衍生的多肽是如何 使用小鼠临床前模型，当外源性给药时，IMPACT实验诱导了类风湿关节炎。POP2 多肽疗法代表了一种新的治疗方法，通过 抑制NF-B信号通路和炎症体通路。人类免疫缺陷病毒的免疫学和分子基础 我们的假设源于我们公布的初步数据，显示了天然表达的、无毒的 POP2多肽在不影响宿主免疫的情况下抑制炎症反应中细胞因子的产生。 我们的研究将为基于POP2多肽疗法的治疗方案如何被利用或 改进后的。疾病的体外表征、剂量递增研究和体内评估 参数将为开发POP2多肽作为一种新的治疗方法提供信息。

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.