Mechanistic Role of CD36 in Thrombosis

CD36 在血栓形成中的机制作用

基本信息

批准号：
8856644
负责人：
Roy L Silverstein
金额：
$ 42.23万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8856644
关键词：
Affect Antioxidants Atherosclerosis Autoimmune Process Biology Bleeding time procedure Blood Blood Circulation 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 Health Hemostatic function Human Hyperlipidemia 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 Systemic disease Tail Testing Therapeutic Intervention Thrombosis Thrombus Toll-like receptors United States Vav guanine-nucleotide exchange factor Veins cell behavior clinically significant imaging system in vitro Model in vivo in vivo Model macrophage migration mortality novel oxidant stress oxidized low density lipoprotein prevent programs receptor scavenger receptor src-Family Kinases

项目摘要

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）：临床上重要的血小板事件是许多与慢性炎症有关的全身性疾病的常见并发症，包括动脉粥样硬化和糖尿病。这些威胁生命的血栓中的许多发生在动脉循环中，与不适当的血小板激活有关。该提案将检验新的假设，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联系起来“高反应性”，从而将其与血栓形成的风险增加。使用小鼠血栓形成模型以及原代人和小鼠细胞发表和初步研究将CD36鉴定为血小板信号受体，它识别并响应炎症过程中产生的内源性“危险信号”，包括氧化的LDL，晚期糖化的蛋白质和细胞衍生的微颗粒。鉴定了一个特定的CD36触发信号通路，涉及由SRC激酶，MAP激酶和VAV家族核苷酸核苷酸交换因子组成的激活信号传导复合物的募集/组装，并证明是与其他血小板途径的独特之处。该提案将检验以下假设：CD36与“危险信号”配体触发的信号级联反应会促进一种独特的“超敏”血小板表型，从而导致体内促触性状态。 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。在剪切和新型体内血栓形成模型下使用微流体的体外血小板功能模型的复杂成像系统将被利用，以将CD36特异性信号通路连接到相关的促性促性效应的机制。将定义其他血小板促和抗激活途径的相互影响，以揭示新的协同作用和相互作用。体内模型将用于测试以下假说：CD36特异性内源性危险信号配体通过与收件人（如受体（如受体）和细胞特异性作用F CD36在体内促进血栓形成在体内促进血栓形成在体内促进血栓形成的作用促进血栓形成，并将使用针对性的遗传降解和氧化疗法来确定体内和氧化应激的设置。