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）：临床显著血栓形成事件是许多与慢性炎症相关的全身性疾病（包括动脉粥样硬化和糖尿病）的常见并发症。许多危及生命的血栓发生在动脉循环中，与血小板活化不当有关。该提案将测试新的假设，即B型清道夫受体CD 36在功能上将代谢和氧化应激与血小板“高反应性”联系起来，从而增加血栓形成的风险。使用小鼠血栓形成模型和原代人类和小鼠细胞的已发表和初步研究将CD 36鉴定为血小板信号传导受体，其识别并响应炎症期间产生的内源性“危险信号”，包括氧化LDL、晚期糖化蛋白和细胞衍生微粒。血小板中一种特异性CD 36触发的信号传导途径涉及由Src激酶、MAP激酶和Vav家族鸟嘌呤核苷酸交换因子组成的活化信号传导复合物的募集/组装，并被鉴定为不同于其他血小板途径。该提议将检验由CD 36与“危险信号”配体接合触发的信号级联促进独特的“超敏”血小板表型的假说，所述血小板表型有助于体内血栓形成前状态。CD 36激活特定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定义。使用剪切下血小板功能的微流体体外模型和新型体内血栓形成模型的复杂成像系统将被用于将CD 36特异性信号传导途径与相关促血栓形成作用的机制连接起来。将定义其他血小板促活化和抗活化途径对CD 36途径的相互影响，以揭示新的协同作用和相互作用。体内模型将用于检验以下假设：CD 36特异性内源性危险信号配体通过与toll样受体的功能性相互作用促进血栓形成，并且将使用靶向遗传缺失和骨髓移植策略以及体内炎症和血栓形成模型来确定在代谢和氧化应激的情况下CD 36在体内促进血栓形成中的细胞特异性作用。