Mechanistic Role of CD36 in Thrombosis

CD36 在血栓形成中的机制作用

• 批准号: 8509398
• 负责人: Roy L Silverstein
• 金额: $ 36.89万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509398
• 关键词: Affect; Antioxidants; Atherosclerosis; Autoimmune Process; Biology; Bleeding time procedure; Blood; Blood Circulation; Blood Clot; Blood Platelets; Blood Vessels; Blood coagulation; Bone Marrow Transplantation; CD36 gene; Carotid Artery Injuries; Cell membrane; Cells; Chronic; Complex; Coupled; Data; Diabetes Mellitus; Disease; Environment; Event; Family; Generations; Genetic; Genome; Goals; Guanine Nucleotide Exchange Factors; Hemostatic function; Human; Hyperlipidemia; Image; Immune system; Inflammation; Inflammation Mediators; Inflammatory; Injury; Investigation; Knockout Mice; Laboratories; Life; Ligands; Link; Malignant Neoplasms; Measures; Metabolic Diseases; Metabolic stress; Microfluidics; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Mus; NADPH Oxidase; National Heart, Lung, and Blood Institute; Obesity; Oxidants; Oxidative Stress; Pathway interactions; Patients; Phenotype; Platelet Activation; Process; Proteins; Publishing; Reagent; Receptor Cell; Receptor Signaling; Regulation; Rheumatologic Disorder; Risk; Role; SR-BI receptor; Series; Signal Pathway; Signal Transduction; Site; Surface; System; Systemic disease; Tail; Testing; Therapeutic Intervention; Thrombosis; Thrombus; Toll-like receptors; United States; Vav guanine-nucleotide exchange factor; Veins; cell behavior; clinically significant; in vitro Model; in vivo; in vivo Model; macrophage; migration; mortality; novel; oxidant stress; oxidized low density lipoprotein; prevent; programs; public health relevance; receptor; scavenger receptor; src-Family Kinases

DESCRIPTION (provided by applicant): Clinically significant thrombotic events are common complications of many systemic diseases associated with chronic inflammation, including atherosclerosis and diabetes. Many of these life- threatening thrombi occur in the arterial circulation and relate to inappropriate platelet activation. This proposal will test the novel hypothesis that the type B scavenger receptor CD36 functionally links metabolic and oxidant stress to platelet "hyper-reactivity" and thus to the increased risk of thrombosis. Published and preliminary studies using mouse thrombosis models and primary human and mouse cells identified CD36 as a platelet signaling receptor that recognizes and responds to endogenous "danger signals" generated during inflammation, including oxidized LDL, advanced glycated proteins, and cell-derived microparticles. A specific CD36-triggered signaling pathway in platelets involving recruitment/assembly of an activated signaling complex made up of Src kinases, MAP kinases, and Vav family guanine nucleotide exchange factors was identified and shown to be unique from other platelet pathways. This proposal will test the hypothesis that signaling cascades triggered by CD36 engagement with "danger signal" ligands promote a unique "hypersensitive" platelet phenotype that contributes to a pro-thrombotic state in vivo. The mechanisms by which CD36 activates specific platelet signaling pathways to regulate cytoskeletal functions and oxidative stress will be defined. Sophisticated imaging systems using a microfluidic in vitro model of platelet function under shear and novel in vivo thrombosis models will be exploited to connect CD36-specific signaling pathways to the mechanisms of the related pro-thrombotic effect. Reciprocal influences of other platelet pro- and anti-activation pathways on the CD36 pathway will be defined to reveal novel synergies and interactions. In vivo models will be used to test the hypothesis that CD36-specific endogenous danger signal ligands promote thrombosis via functional interactions with toll like receptors and the cell-specific role f CD36 in promoting thrombosis in vivo in the setting of metabolic and oxidant stress will be determined using targeted genetic deletion and bone marrow transplantation strategies with in vivo models of inflammation and thrombosis.

描述(由申请人提供)：临床上重要的血栓形成事件是许多与慢性炎症相关的系统性疾病的常见并发症，包括动脉粥样硬化和糖尿病。其中许多危及生命的血栓发生在动脉循环中，与不适当的血小板激活有关。这项提议将检验新的假设，即B型清道夫受体CD36在功能上将代谢和氧化剂应激与血小板“高反应性”联系起来，从而增加血栓形成的风险。利用小鼠血栓形成模型以及原代人类和小鼠细胞进行的已发表和初步研究发现，CD36是一种血小板信号受体，可以识别炎症过程中产生的内源性“危险信号”并对其做出反应，包括氧化的低密度脂蛋白、高级糖化蛋白和细胞衍生的微粒。在血小板中发现了一个由CD36触发的信号通路，该通路涉及由Src激酶、MAP激酶和Vav家族鸟嘌呤核苷酸交换因子组成的激活的信号复合体的募集/组装，并被证明是不同于其他血小板通路的。这项提议将检验一种假说，即CD36与“危险信号”配体的接触所触发的信号级联促进了一种独特的“超敏”血小板表型，从而在体内促进了血栓前状态。CD36激活特定的血小板信号通路以调节细胞骨架功能和氧化应激的机制将被确定。利用剪切力下血小板功能的微流控体外模型和新的体内血栓形成模型的复杂成像系统将被用来连接CD36特异的信号通路和相关的促血栓形成作用的机制。CD36通路上的其他血小板激活途径和抗激活途径的相互影响将被定义，以揭示新的协同作用和相互作用。体内模型将被用来检验CD36特异性内源性危险信号配体通过与Toll样受体的功能相互作用促进血栓形成的假设，以及CD36在代谢和氧化应激环境中促进体内血栓形成的细胞特异性作用将通过体内炎症和血栓形成的模型来确定。