IRAK4 and systemic lupus erythematosus

描述(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、抗疟疾或消炎药治疗SLB患者的疗效有限。FDA批准的Benlysta是一种人类抗B淋巴细胞刺激因子的单抗，可以降低SLE患者的疾病严重程度，但非裔美国人的患者对治疗没有反应。此外，Benlysta引起了严重的副作用，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的发生，靶向TLRs是一种很有前途的策略。几个TLR(TLR2、TLR4、TLR7-9)参与了SLE，表明靶向一个TLR会使其他TLR启动的信号通路不受影响。这种冗余性决定了需要对常见的TLR信号通路进行更全球化的靶向治疗干预。由于IRAK4是一种关键的激酶，它启动了与SLE相关的所有TLR的信号传递，我们假设IRAK4活性的增加是狼疮的关键决定因素，而IRAK4活性的减弱将缓解促进狼疮的TLR通路，提供对SLE的保护，同时保留IRAK4接头功能，促进抗菌素耐药性。这一假设将在以下具体目标中进行检验：1.确定IRAK4在狼疮易感小鼠狼疮进展过程中的表达和活性；以及2.设计和测试IRAK4的多肽抑制剂，以确定其阻断狼疮易感小鼠系统性红斑狼疮的能力。我们希望确定IRAK4表达和活性的变化是否导致小鼠系统性红斑狼疮的发生，通过将IRAK4激酶失活的小鼠与易患狼疮的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诱骗多肽拮抗剂在小鼠中抑制狼疮的效用。该项目有望提供原则验证结果，以促进我们对IRAK4信号在SLE中的理解，并为未来的RO1拨款提供概念性框架，以系统分析IRAK4在SLE中的表达和活性。它将促进计算机辅助设计抑制IRAK4的小分子成分，并将为未来在SLE患者中进行翻译研究铺平道路。这些进展将对系统性红斑狼疮的基础免疫学和改善美国狼疮患者的公共健康具有关键意义。

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.