Role of IRAK-4 in Rheumatoid Arthritis

IRAK-4 在类风湿关节炎中的作用

基本信息

批准号：
9135224
负责人：
ANDREI E MEDVEDEV
金额：
$ 23.93万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9135224
关键词：
Accounting Address Adult Adverse reactions Affect Animal Disease Models Animal Model Anti-Inflammatory Agents Anti-inflammatory Area Arthritis Attenuated Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity Automobile Driving Cells Cessation of life Communicable Diseases Data Development Discrimination Disease Engineering Equilibrium Etiology Future Genes Genetic Polymorphism Genetic Transcription Grant Health Human IRAK1 gene IRAK3 gene IRAK4 gene Immune Immunology Inflammation Inflammation Mediators Inflammatory Inflammatory Arthritis Interferon-beta Interleukin-1 beta Intervention Link MAP3K7 gene Mediating Metalloproteases Modality Modeling Molecular Mus MyD88 protein Myelogenous National Institute of Allergy and Infectious Disease Natural Immunity Pathogenesis Pathway interactions Patients Peptides Pharmaceutical Preparations Phosphotransferases Public Health Receptor Activation Receptor Signaling Regulation Reporting Research Rheumatoid Arthritis Role Serum Severities Signal Pathway Signal Transduction TLR2 gene TLR3 gene TLR4 gene TLR7 gene Testing Therapeutic Therapeutic Intervention Toll-Like Receptor Pathway Toll-like receptors Translational Research antimicrobial attenuation base cytokine design improved inhibitor/antagonist insight kinase inhibitor microbial mouse model novel novel strategies novel therapeutic intervention novel therapeutics prevent public health relevance receptor receptor expression receptor-mediated signaling response sensor small molecule small molecule inhibitor

项目摘要

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.

描述（由申请人提供）：类风湿性关节炎（RA）是一种无法治愈的自身免疫性疾病，对美国的健康构成重大威胁。传统的 RA 治疗方法（例如非类固醇抗炎药）经常引起不良反应且疗效有限。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，RA 患者中 TLR 表达和反应性增加就证明了这一点。然而，在该疾病的小鼠模型中，以及 TLR2-/-、TLR4-/- 和骨髓分化初级反应蛋白 (MyD88)-/- 小鼠中 RA 严重程度的降低，RA 中 TLR 反应过度的分子基础尚不清楚Interleukin-1 受体相关激酶 (IRAK) 4 是所有利用 MyD88 途径的 TLR 使用的中心激酶。基于 RA 中过度的 TLR 信号传导，其作用如下。这些反应中的 TLR-MyD88-IRAK4 信号轴，以及 IRAK1 多态性与人类 RA 的关联，IRAK4 的旺盛激活可能是 RA 发展的基础，而 IRAK4 活性的调节可能代表了一种新的治疗方式，我们追求增加 IRAK4。由于正调节因子 (Pellino-1) 和负调节因子 (IRAK-M、Pellino-3b) 的扭曲控制，激活是 RA 的关键驱动因素IRAK4 活性的减弱将减轻促进疾病的 TLR 途径，该假设将在以下具体目标中得到检验： 1. 确定 IRAK4 在 RA 患者的 Mfs 中以及炎症性关节炎进展过程中引发疾病相关炎症介质的作用。在小鼠模型中；2. 设计 IRAK4 肽拮抗剂并测试其抑制小鼠炎症性关节炎的能力。原理验证结果揭示了 IRAK4 激活的改变调节在 RA 发病机制中的作用，并探索了新型细胞渗透性 IRAK4 肽拮抗剂在减轻小鼠关节炎方面的用途，这将为未来的 RO1 提案铺平道路。在 RA 患者和关节炎小鼠模型中进行深入全面的转化研究，并为合理设计 IRAK4 激活抑制剂作为 RA 的新治疗方式提供概念框架。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。