Role of IRAK-4 in Rheumatoid Arthritis

 描述（由申请人提供）：风湿性关节炎（RA）是一种无法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，例如非类固醇抗炎药，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（TLR）参与RA，如RA患者和疾病小鼠模型中TLR表达和反应性增加，以及TLR 2-/-、TLR 4-/-和髓样分化初级反应蛋白（MyD 88）-/-小鼠中RA严重程度降低所证明。然而，类风湿关节炎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是所有利用MyD 88途径的TLR使用的中心激酶。基于RA中过度的TLR信号传导，TLR-MyD 88-IRAK 4信号传导轴在这些反应中的作用，以及IRAK 1多态性与人类RA的相关性，IRAK 4的过度激活可能是RA发展的基础，并且IRAK 4活性的调节可能代表一种新的治疗方式。我们假设，由于阳性（Pellino-1）和阴性（IRAK-M，Pellino-3b）调节剂的扭曲控制，IRAK 4活化增加是RA的关键驱动因素，IRAK 4活性的减弱将减轻促进疾病的TLR途径。这一假设将在以下具体目标中得到检验：1.确定IRAK 4在RA患者Mfs中以及在小鼠模型中炎症性关节炎进展期间引发疾病相关炎症介质中的作用; 2.工程化IRAK 4肽拮抗剂并测试其抑制小鼠炎症性关节炎的能力。该探索性/开发性R21项目将提供新的原理验证结果，以揭示IRAK 4活化的调节改变在RA发病机制中的作用，并探索新型细胞渗透性IRAK 4肽拮抗剂减轻小鼠关节炎的效用。它将为未来的RO 1提案铺平道路，该提案旨在对RA患者和关节炎小鼠模型进行深入全面的转化研究，并为合理设计IRAK 4激活抑制剂作为RA的新治疗方式提供概念框架。这些进展对于RA和其他自身免疫性疾病的基础免疫学以及改善美国RA患者的公共健康至关重要。

 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.