Role of IRAK-4 in Rheumatoid Arthritis

 描述(申请人提供)：类风湿性关节炎(RA)是一种不可治愈的自身免疫性疾病，在美国对健康构成重大威胁。传统的RA治疗方法，如非类固醇抗炎药，通常会引起不良反应，疗效有限，需要开发新的治疗策略。越来越多的证据支持Toll样受体(TLRs)参与了RA的发病，在RA患者和小鼠模型中，TLR的表达和反应性增加，TLR2-/-、TLR4-/-和髓系分化主要反应蛋白(MyD88)-/-小鼠的RA严重程度降低。然而，类风湿关节炎患者TLR反应过度的分子基础尚不清楚。白细胞介素1受体相关激酶(IRAK)4是所有TLR通过MyD88途径使用的一种中央激酶。根据RA中过多的TLR信号，TLR-MyD88-IRAK4信号轴在这些反应中的作用，以及IRAK1基因多态性与RA的关联，IRAK4的激活可能是RA发生的基础，调节IRAK4的活性可能代表一种新的治疗方式。我们假设，由于正(Pellino-1)和负(IRAK-M，Pellino-3b)调节因子的扭曲控制，IRAK4活性增加是RA的关键驱动因素，IRAK4活性的减弱将缓解致病TLR途径。这一假说将在以下特定目标进行验证：1.确定IRAK4在RA患者的MFS中诱导疾病相关炎症介质以及在小鼠炎性关节炎模型进展过程中的作用；2.设计IRAK4多肽拮抗剂并测试它们抑制小鼠炎性关节炎的能力。这一探索性/发展中的R21项目将提供新的原理证明结果，以揭示IRAK4激活调节改变在RA发病机制中的作用，并探索新型细胞渗透性IRAK4肽拮抗剂在减轻小鼠关节炎方面的应用。这将为未来的RO1提案铺平道路，该提案旨在对RA患者和小鼠关节炎模型进行深入的全面翻译研究，并为合理设计IRAK4激活的抑制剂作为RA的新治疗方式提供概念框架。这些进展将对RA和其他自身免疫性疾病的基础免疫学以及改善美国RA患者的公共健康具有关键意义。

 DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an incurable autoimmune disease that poses a significant health threat in the U.S. Traditional approaches for RA treatment, e.g. non-steroid anti-inflammatory drugs, often cause adverse reactions and have limited efficacy, requiring the development of new therapeutic strategies. Accumulating evidence supports the involvement of Toll-like receptors (TLRs) in RA, as evidenced by increased TLR expression and responsiveness in RA patients and in mouse models of the disease, and decreased RA severity in TLR2-/-, TLR4-/-, and myeloid differentiation primary response protein (MyD88)-/- mice. However, the molecular basis of exaggerated TLR responses in RA is unclear. Interleukin-1 receptor-associated kinase (IRAK) 4 is a central kinase used by all TLR utilizing the MyD88 pathway. Based on excessive TLR signaling in RA, the role of TLR-MyD88-IRAK4 signaling axis in these responses, and association of IRAK1 polymorphisms with RA in humans, it is possible that exuberant activation of IRAK4 underlies RA development, and regulation of IRAK4 activity could represent a novel therapeutic modality. We hypothesize that increased IRAK4 activation, due to distorted control by positive (Pellino-1) and negative (IRAK-M, Pellino-3b) regulators, is a critical driver of RA and that attenuation of IRAK4 activity will mitigate disease-promoting TLR pathways. This hypothesis will be tested in the following Specific Aims: 1. Define the role of IRAK4 in eliciting disease-associated inflammatory mediators in Mfs from RA patients and during progression of inflammatory arthritis in mouse models; 2. Engineer IRAK4 peptide antagonists and test their ability to inhibit inflammatory arthritis in mice. This exploratory/developmental R21 project will provide new proof-of-principle results to uncover the role of altered regulation of IRAK4 activation in the pathogenesis of RA and exploring the utility of novel cell- permeable IRAK4 peptide antagonists to attenuate arthritis in mice. It will pave the way for a future RO1 proposal aimed at in-depth comprehensive translational research in RA patients and mouse models of arthritis and provide the conceptual framework for rational design of inhibitors of IRAK4 activation as a new therapeutic modality for RA. These advances would be of key importance for basic immunology of RA and other autoimmune diseases and for improving public health of RA patients in the U.S.