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是一种针对B淋巴细胞刺激因子的人单克隆抗体，可降低SLE患者的疾病严重程度，但非裔美国人患者对治疗无反应。此外，Benlysta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（TLR）参与SLE，靶向TLR是一种有前途的策略。几种TLR（TLR 2、TLR 4、TLR 7 -9）参与SLE，表明靶向一种TLR将使由其他TLR启动的信号通路不受影响。这种冗余决定了需要更全面地靶向常见TLR信号传导途径以进行治疗干预。由于IRAK 4是一种关键激酶，可通过SLE中涉及的所有TLR启动信号传导，因此我们假设IRAK 4活性增加是狼疮的关键决定因素，并且IRAK 4活性的减弱将减轻促进狼疮的TLR途径，提供针对SLE的保护，同时保留有助于抗菌素耐药性的IRAK 4衔接子功能。该假设将在以下具体目标中进行检验：1.定义狼疮易感小鼠中SLE进展期间IRAK 4的表达和活性;和2.工程和测试IRAK 4的肽抑制剂在狼疮易感小鼠中阻断SLE的能力。我们希望确定IRAK 4表达和活性的改变是否是小鼠SLE发生的基础，通过将IRAK 4激酶失活的小鼠与狼疮易感的Fc <$R2b-/- Yaa小鼠杂交，从机制上确定IRAK 4激酶活性的作用，并确定新的IRAK 4诱饵肽拮抗剂在抑制小鼠狼疮中的效用。该项目预计将提供原理验证结果，以促进我们对SLE中IRAK 4信号传导的理解，并为未来的RO 1资助产生概念框架，以系统地分析IRAK 4表达和活性在SLE中的作用。这将有助于计算机辅助设计抑制IRAK 4的小分子组分，并为SLE患者的未来转化研究铺平道路。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至关重要。

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.