Arrestins in TLR4 Signaling in Macrophages

描述（由申请人提供）：巨噬细胞产生促炎细胞因子显著促进许多炎性疾病（包括关节炎）的发病机制。因此，了解参与巨噬细胞促炎分子表达调节的信号传导机制对于开发对抗炎性疾病的药物至关重要。最近的研究表明，Toll样受体（TLR）参与了许多人类疾病中炎症的启动和维持。特别重要的是TLR 4的作用，其关键地调节细胞因子的产生，因此是炎性疾病中的药物靶标。因此，了解TLR 4刺激的信号通路影响炎症分子表达的生化机制是非常重要的。最近的研究表明，非视觉arrestins（ARR 2和ARR 3）在调节TLR信号和病理生理学中的关键作用。Arrestins（ARRs）是一种支架蛋白，最初发现它们在G蛋白偶联受体（GPCR）脱敏中起作用.有证据表明，ARR 2和3与不同的蛋白质相互作用，从而调节巨噬细胞和小鼠体内TLR 4信号传导和炎症基因表达。本申请的目的是了解ARR 2和ARR 3调节巨噬细胞中TLR 4信号传导的生化机制，并测试这与小鼠炎症的关系。为了实现这一目标，我们将测试以下假设：（a）ARR 2和3在巨噬细胞中的TLR 4信号传导和炎症介质产生中起关键作用，和（B），这通过不同的蛋白质-蛋白质相互作用发生，和（c）ARR 2和3在小鼠体内关键地参与TLR 4介导的炎症反应。我们的研究应该提供重要的洞察TLR 4信号在巨噬细胞的机制，以及提供潜在的治疗策略，针对TLR 4信号在各种炎症性疾病。公共卫生相关性：巨噬细胞中的Toll样受体-4活化在各种炎症性疾病的发展中起重要作用。本申请的主要目的是了解巨噬细胞中TLR 4刺激的信号通路的调节，并测试其与炎症性疾病的关系。

DESCRIPTION (provided by applicant): Production of proinflammatory cytokines by macrophages significantly contributes to the pathogenesis of many inflammatory diseases including arthritis. Therefore, understanding the signaling mechanisms involved in the regulation of expression of pro-inflammatory molecules by macrophages is pivotal to developing drugs to combat inflammatory diseases. Recent studies have implicated Toll-like receptors (TLRs) in the initiation and maintenance of inflammation in a number of human diseases. Of particular importance is the role of TLR4, which critically regulates cytokine production and is therefore a drug target in inflammatory diseases. Hence, understanding the biochemical mechanisms by which TLR4-stimulated signaling pathways affect expression of inflammatory molecules is highly significant. Recent studies have demonstrated a critical role for non-visual arrestins (ARR2 and ARR3) in the regulation of TLR signaling and pathophysiology. Arrestins (ARRs) are scaffolding proteins originally discovered for their role in G- protein coupled receptor (GPCR) desensitization. Evidence indicates that ARR2 and 3 interact with distinct proteins and consequently regulate TLR4 signaling and inflammatory gene expression in macrophages and in vivo in mice. The objective of this application is to understand the biochemical mechanisms by which ARR2 and ARR3 regulate TLR4 signaling in macrophages and to test how this relates to inflammation in mice. To accomplish this objective, we will test the following hypotheses: (a) ARR2 and 3 play a crucial role in TLR4 signaling, and inflammatory mediator production in macrophages, and (b), this occurs via distinct protein-protein interactions, and (c) ARR2 and 3 are critically involved in TLR4-mediated inflammatory response in mice in vivo. Our studies should provide important insight into the mechanisms of TLR4 signaling in macrophages as well as provide potential therapeutic strategies for targeting TLR4 signaling in a variety of inflammatory diseases. PUBLIC HEALTH RELEVANCE: Toll-like receptor-4 activation in macrophages plays an important role in the development of various inflammatory diseases. Major objective of this application is to understand the regulation of TLR4-stimulated signaling pathways in macrophages and test as to how it relates to inflammatory diseases.