MRP-14, CD36 and Thrombosis

MRP-14、CD36 和血栓形成

基本信息

批准号：
9025295
负责人：
Daniel I Simon
金额：
$ 51.97万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9025295
关键词：
Activated Partial Thromboplastin Time measurement Acute myocardial infarction Adhesions Affect Animals Antibodies Arterial Fatty Streak Atherosclerosis Binding Bleeding time procedure Blood Platelets Blood coagulation CD36 gene Calcium Cardiovascular Diseases Cardiovascular system Carotid Arteries Cause of Death Clinical Research Collaborations Collagen Complex Coronary DNA Deep Vein Thrombosis Developed Countries Disease Event Family member Future Generations Genes Genetic Genome Health Hemorrhage Hemostatic function High Fat Diet Infusion procedures Leukocytes Low-Density Lipoproteins Mediating Membrane Michigan Modeling Molecular Mus Myocardial Infarction Observational Study Pathway interactions Patients Peptides Plasma Platelet Activation Prevention Protein Family Publishing Reporting Risk Role S100A8 gene S100A9 gene SNP genotyping Sampling Siblings Signal Transduction Source Stroke Tail Tertiary Protein Structure Therapeutic Thrombin Thrombosis Thrombus Time VWF gene Venous Venous Thrombosis Whole Blood acute coronary syndrome aged artery occlusion atherothrombosis base cardiovascular risk factor case control cohort college extracellular genetic analysis genome wide association study high risk insight low density lipoprotein inhibitor molecular domain new therapeutic target novel prospective public health relevance receptor research study validation studies vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Thrombotic cardiovascular (CV) diseases, including heart attack (MI), stroke and deep venous thrombosis (DVT), are the leading cause of death in developed countries. Using transcriptional profiling of platelets, we identified the S100 calcium-modulated protein family member MRP-14 (S100A9) as an acute MI gene. Case- control validation studies demonstrated that elevated plasma levels of MRP-8/14 complexes predict increased risk of future CV events. Studies using MRP-14-/- mice determined that MRP-8/14 broadly regulates vascular inflammation. However, a key unanswered question is whether MRP-8/14 participates directly in thrombosis. In a recent report (Wang et al. J Clin Invest 2014), we showed that the time to arterial thrombotic occlusion was prolonged markedly in MRP-14-/- mice. We observed that MRP-14 and MRP-8/14 are expressed in and secreted by platelets, and that thrombus formation is reduced in whole blood from MRP-14-/- mice. Infusion of WT platelets or purified MRP-14 into MRP-14-/- mice shortened the carotid artery occlusion time, indicating that platelet-derived MRP-14 directly regulates thrombosis. We next identified CD36 as the platelet membrane receptor for MRP-14. Importantly, while deficiency of MRP-14 is protective of thrombosis, it has no effect on multiple parameters of hemostasis. The central hypotheses of this project are that platelet MRP-14 regulates arterial and venous thrombosis in a CD36-dependent manner, that this interaction can be exploited to develop a safer anti-thrombotic agent (i.e., reduced bleeding risk), and that plasma MRP- 8/14 levels are genetically determined and modified by CV disease activity. We propose 3 specific aims. First, we will characterize the molecular domains responsible for MRP-14:CD36 binding and the downstream signaling that leads to platelet activation. Second, we will investigate the role of MRP-14 in venous thrombosis and in arterial thrombosis in the context of atherosclerosis. Third, major genetic, cellular, and CV disease activity determinants of plasma MRP-8/14 concentration will be explored in collaboration with the Genes and Blood Clotting Study. The MRP-14:CD36 interaction represents a novel target for treating cardiovascular disorders, including heart attack stroke, and DVT. The results of these studies will provide important insights to exploit this interaction to influence thrombosis, but not hemostasis (i.e., reduced bleeding risk).

描述（由申请人提供）：血栓性心血管 (CV) 疾病，包括心脏病 (MI)、中风和深静脉血栓 (DVT)，是发达国家的主要原因。通过血小板转录分析，我们确定了 S100。钙调节蛋白家族成员 MRP-14 (S100A9) 作为急性 MI 基因病例对照验证研究表明，血浆 MRP-8/14 复合物水平升高预示风险增加。使用 MRP-14-/- 小鼠的研究确定 MRP-8/14 广泛调节血管炎症，但一个未解答的关键问题是 MRP-8/14 是否直接参与血栓形成。等人 J Clin Invest 2014），我们发现 MRP-14-/- 小鼠的动脉血栓闭塞时间显着延长。 MRP-8/14 在血小板中表达并由血小板分泌，MRP-14-/- 小鼠的全血中血栓形成减少，将 WT 血小板或纯化的 MRP-14 输注至 MRP-14-/- 小鼠体内可缩短血栓形成时间。颈动脉闭塞时间，表明血小板源性 MRP-14 直接调节血栓形成，重要的是，我们接下来确定 CD36 是 MRP-14 的血小板膜受体。 MRP-14 对血栓形成有保护作用，对止血的多个参数没有影响该项目的中心假设是血小板 MRP-14 以 CD36 依赖性方式调节动脉和静脉血栓形成，可以利用这种相互作用来开发。更安全的抗血栓药物（即降低出血风险），并且血浆 MRP-8/14 水平由遗传决定并由心血管疾病活动性改变。我们提出了 3 个具体目标。首先，我们将表征负责 MRP-14:CD36 结合的分子结构域和导致血小板激活的下游信号传导。其次，我们将研究 MRP-14 在动脉粥样硬化背景下的静脉血栓形成和动脉血栓形成中的作用。第三，将与基因和血液凝固研究合作探索血浆 MRP-8/14 浓度的主要遗传、细胞和心血管疾病活动决定因素。MRP-14:CD36 相互作用代表了一种机制。治疗心血管疾病（包括心脏病、中风和深静脉血栓）的新靶标。这些研究的结果将为利用这种相互作用影响血栓形成而不是止血（即降低出血风险）提供重要见解。