IRAK4 and systemic lupus erythematosus

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种严重的自身免疫性疾病，影响全球500万人。用皮质类固醇、抗疟药或抗炎药治疗SLB患者的疗效有限。fda批准的Benlysta是一种抗b淋巴细胞刺激剂的人单克隆抗体，可降低SLE患者的疾病严重程度，但非裔美国患者对治疗没有反应。此外，本利司他还会引起严重的副作用，如严重感染、恶心、腹泻和发烧。因此，迫切需要开发新的狼疮治疗策略。越来越多的证据支持toll样受体（TLRs）参与SLE，靶向TLRs是一种很有前途的策略。多个TLR （TLR2, TLR4, TLR7-9）参与SLE，表明靶向一个TLR不会影响其他TLR启动的信号通路。这种冗余表明需要更全面地针对常见的TLR信号通路进行治疗干预。由于IRAK4是激活与SLE相关的所有TLR信号传导的关键激酶，我们假设IRAK4活性的增加是狼疮的关键决定因素，而IRAK4活性的衰减将减轻狼疮促进TLR通路，提供对SLE的保护，同时保留有助于抗菌素耐药性的IRAK4适配器功能。假设将在以下具体目标中进行检验：1。确定狼疮易感小鼠SLE进展过程中IRAK4的表达和活性和2。设计并测试IRAK4肽抑制剂在狼疮易感小鼠中阻断SLE的能力。我们希望确定IRAK4表达和活性的改变是否在小鼠SLE的发展中起作用，通过将IRAK4激酶失活的小鼠与狼疮易发的Fc¿R2b-/- Yaa小鼠杂交，从机制上确定IRAK4激酶活性的作用，并确定新的IRAK4诱变肽拮抗剂在抑制狼疮小鼠中的效用。该项目预计将提供原理验证结果，以促进我们对IRAK4信号在SLE中的理解，并为未来的RO1拨款提供概念框架，以系统地分析IRAK4表达和活性在SLE中的作用。它将促进计算机辅助设计抑制IRAK4的小分子成分，并为未来SLE患者的转化研究铺平道路。这些进展对于SLE的基础免疫学和改善美国狼疮患者的公共健康具有重要意义

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a severe autoimmune disease that affects 5 million people worldwide. Treatment of SLB patients with corticosteroids, antimalarial, or anti-inflammatory drugs have limited efficacy. FDA-approved Benlysta, a human monoclonal antibody against B-lymphocyte stimulator, decreased disease severity in SLE patients, but African American patients did not respond to treatment. Furthermore, Benlysta caused significant side effects such as severe infections, nausea, diarrhea, and fever. Thus, there is an urgent need to develop new therapeutic strategies for lupus. Accumulating evidence supports the involvement of Toll-like receptors (TLRs) in SLE, and targeting TLRs is a promising strategy. Several TLRs (TLR2, TLR4, TLR7-9) are involved in SLE, indicating that targeting one TLR would leave signaling pathways initiated by other TLRs unaffected. This redundancy dictates the need for a more global targeting of common TLR signaling pathways for therapeutic intervention. Since IRAK4 is a critical kinase that initiates signaling by all TLRs implicated in SLE, we hypothesize that increased IRAK4 activity is the critical determinant of lupus and that attenuation of IRAK4 activity will mitigate lupus-promoting TLR pathways, providing protection against SLE, while preserving IRAK4 adapter functions that contribute to antimicrobial resistance. The hypothesis will be tested in the following Specific Aims to: 1. Define IRAK4 expression and activity during progression of SLE in lupus-prone mice; and 2. Engineer and test peptide inhibitors of IRAK4 for their ability to block SLE in lupus-prone mice. We expect to define if altered IRAK4 expression and activity underlies development of SLE in mice, mechanistically define the role of IRAK4 kinase activity by crossing IRAK4 kinase-inactive mice with lupus-prone Fc¿R2b-/- Yaa mice, and determine the utility of new IRAK4 decoy peptide antagonists for inhibiting lupus in mice. This project is expected to provide proof-of-principle results to advance our understanding of IRAK4 signaling in SLE, and to generate the conceptual framework for a future RO1 grant to systematically analyze the role of IRAK4 expression and activity in SLE. It will facilitate computer-assisted design of small molecular components to inhibit IRAK4, and will pave the way for future translational research in SLE patients. These advances would be of key importance for basic immunology of SLE, and for improving public health of lupus patients in the U.S.