Mechanisms of CD36 Signal Transduction - Resubmission - 1

描述（由申请人提供）：动脉粥样硬化和2型糖尿病的发病率在全球范围内持续增加，开发代谢性疾病的新疗法至关重要。值得注意的是，这两种疾病都与以细胞因子，特别是白细胞介素-1b表达增加为特征的低度全身性炎症有关。虽然内源性配体对先天免疫系统的慢性刺激被认为是这些代谢性疾病的基础，但激活的分子机制仍不清楚。先天免疫传感器的Nod样受体（NLR）家族，如NLRP 3炎性体，识别某些危险信号，导致半胱天冬酶-1活化以及IL-1家族细胞因子的加工和分泌。该途径受到高度调控，需要炎性小体“引发”和“激活”的两次打击模型，但内源性配体如何触发这两个步骤尚不清楚。清道夫受体CD 36参与动脉粥样硬化和糖尿病的发病机制，并与多种修饰的内源性配体结合，包括氧化低密度脂蛋白（oxLDL）、饱和脂肪酸、胰岛淀粉样多肽（IAPP）等。值得注意的是，这些配体中的一些最近已被证明是触发炎性小体，我们假设，CD 36的参与可能是一种常见的机制，通过这种胞质复合物的感官代谢相关的危险信号，并导致免疫功能障碍。在这项授权中，我们提出（a）确定通过CD 36和Toll样受体（TLR）的协同信号传导在响应内源性配体“引发”炎性小体（步骤1）中的作用，（B）确定CD 36的参与如何通过内溶酶体功能障碍和活性氧物质的产生直接促进炎性小体的“活化”（步骤2），和（c）测试在动脉粥样硬化和胰岛素抗性/糖尿病的小鼠模型中体内抑制CD 36是否阻断炎性小体活化和IL-1b产生。这些研究将深入了解动脉粥样硬化和糖尿病期间炎症体被触发的机制，并评估CD 36作为治疗慢性炎症的治疗靶点的潜力，这些慢性炎症是这些代谢性疾病的特征。!

DESCRIPTION (provided by applicant): The incidence of atherosclerosis and type 2diabetes continues to increase world-wide, and the development of new therapeutics for metabolic disease is crucial. Notably, both diseases are associated with low grade systemic inflammation characterized by increased expression of cytokines, particularly interleukin-1b. Although chronic stimulation of the innate immune system by endogenous ligands is believed to underlie these metabolic diseases, the molecular mechanisms of activation remain unclear. The Nod-like receptor (NLR) family of innate immune sensors, such as the NLRP3 inflammasome, recognize certain danger signals leading to caspase-1 activation and processing and secretion of IL-1 family cytokines. This pathway is highly regulated and requires a two-hit model of inflammasome "priming" and "activation", but how endogenous ligands trigger these two steps is not clear. The scavenger receptor CD36 been implicated in the pathogenesis of atherosclerosis and diabetes, and binds a variety of modified endogenous ligands that accumulate in these diseases, including oxidized LDL (oxLDL), saturated fatty acids, islet amyloid polypeptide (IAPP). Notably, several of these ligands have recently been shown to be trigger the inflammasome and we hypothesize that engagement of CD36 may be a common mechanism by which this cytosolic complex senses metabolic-associated danger signals and leads to immune dysfunction. In this grant, we propose to (a) determine the role of cooperative signaling via CD36 and Toll-like receptors (TLRs) in "priming" the inflammasome (step 1) in response to endogenous ligands, (b) determine how engagement of CD36 contributes directly to "activation" of the inflammasome (step 2) through endolysosomal dysfunction and production of reactive oxygen species, and (c) test whether inhibition of CD36 in vivo blocks inflammasome activation and IL-1b production in mouse models of atherosclerosis and insulin resistance/diabetes. These studies will provide insight into the mechanisms by which the inflammasome is triggered during atherosclerosis and diabetes, and assess the potential of CD36 as a therapeutic target in the treatment of the chronic inflammation that characterizes these metabolic diseases. !