Mechanisms of CD36 Signal Transduction - Resubmission - 1

描述(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，开发针对代谢性疾病的新疗法至关重要。值得注意的是，这两种疾病都与低度全身炎症有关，其特征是细胞因子，特别是白介素1b的表达增加。尽管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。NOD样受体(NLR)家族的先天免疫感受器，如NLRP3炎症体，识别某些危险信号，导致caspase-1激活和IL-1家族细胞因子的处理和分泌。这一途径受到高度调控，需要炎症体“启动”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CD36参与动脉粥样硬化和糖尿病的发病机制，并与这些疾病中积聚的多种内源性修饰配体结合，包括氧化型低密度脂蛋白(OxLDL)、饱和脂肪酸、胰岛淀粉样多肽(IAPP)。值得注意的是，最近发现这些配体中的几个可以触发炎症小体，我们假设CD36的参与可能是这种胞浆复合体感知代谢相关危险信号并导致免疫功能障碍的常见机制。在这项研究中，我们建议：(A)确定通过CD36和Toll样受体(TLRs)的协同信号在响应内源性配体的“启动”炎症体中的作用(步骤1)，(B)确定CD36的参与如何通过内溶酶体功能障碍和产生活性氧直接促进炎症体的“激活”(步骤2)，以及(C)在小鼠动脉粥样硬化和胰岛素抵抗/糖尿病模型中测试抑制CD36是否阻止炎症体的激活和IL-1b的产生。这些研究将深入了解动脉粥样硬化和糖尿病期间炎症小体被触发的机制，并评估CD36作为治疗慢性炎症的潜力，这些慢性炎症是这些代谢性疾病的特征。好了！

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. !