Characterization of coagulation factor-platelet interactions: role of FXI

凝血因子-血小板相互作用的表征：FXI 的作用

基本信息

批准号：
8449717
负责人：
Owen J McCarty
金额：
$ 43.44万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8449717
关键词：
Adult Affect Animals Apple Binding Binding Sites Biological Assay Bleeding time procedure Blood Blood Coagulation Factor Blood Platelets Blood Vessels Blood flow Cardiovascular Diseases Coagulation Process Collagen Commit Deep Vein Thrombosis Development Disease Disease susceptibility Epidemiology Event Exhibits Factor XI Factor XI Deficiency Factor XIIa Factor XIa Fibrin Fibrinolytic Agents Generations Genetic Glycoprotein Ib Goals Health Hemorrhage Hemostatic function In Vitro Individual Injury Ischemic Stroke Ligands Light Maintenance Mediating Modeling Molecular Mus Myocardial Infarction Oryctolagus cuniculus Pathologic Peptide Hydrolases Pharmacologic Substance Phase Physiological Platelet Glycoproteins Play Population Primates Recombinants Relative (related person)Research Risk Factors Role Solid Stroke Surface System Testing Therapeutic Thrombin Thrombosis Thrombus United States apolipoprotein E receptor 2 base combat design genetic risk factor in vivo inhibitor/antagonist insight mutant neutralizing antibody neutralizing monoclonal antibodies novel oligomycin sensitivity-conferring protein prevent public health relevance receptor reconstitution

项目摘要

DESCRIPTION (provided by applicant): Elevated coagulation factor XI (FXI) level is an independent risk factor for deep vein thrombosis, ischemic stroke, and myocardial infarction. Inherited FXI-deficiency causes mild bleeding tendency, yet it has also been found to be protective against ischemic stroke. FXI has been shown to play a critical role in the formation of experimental thrombi, as evidenced by the fact that genetic deletion or pharmacological inhibition of FXI prevents vascular occlusions in animal thrombosis models. While these findings implicate an important role for FXI in thrombosis, and a possible role in hemostasis, they do not suggest molecular mechanisms by which FXI differentially contributes to (patho)physiological coagulation. Blood platelets are the essential cellular components of primary hemostasis. FXI has been shown to bind specifically to the platelet surface via the platelet glycoprotein (GP) Ib-IX-V complex; however, the functional significance of this interaction is unclear. Moreover, it is unknown whether shear forces due to blood flow play a role in regulating FXI-platelet binding. It has been suggested that GPIb orchestrates the activation of FXI through the protease thrombin; however, there is considerable controversy surrounding this hypothesis. Moreover, while thrombin, activated FXI (FXIa), or activated factor XII (FXIIa), has been shown to activate FXI in purified systems in vitro, the relative importance of these FXI activators on the platelet surface ex vivo or in vivo has not been established. The objectives of our proposed studies are to elucidate the mechanisms of FXI-platelet interactions and to provide further insight into the physiological role of FXI in normal hemostasis and pathologic coagulation. We hypothesize that FXI-platelet interactions promote clot formation under shear flow conditions. We have identified FXI as a ligand for the platelet apolipoprotein E receptor 2 (ApoER2). We hypothesize that ApoER2 plays a critical role in mediating FXI-platelet binding and in initiating coagulation under flow. These hypotheses will be tested through the following specific aims: Aim 1: Determine the molecular mechanisms and consequences of platelet-FXI interactions. Aim 2: Determine the role of FXI-platelet binding in ex vivo thrombus formation. Aim 3: Determine the role of FXI-platelet binding in thrombus formation in vivo. We are committed to the design and development of novel antithrombotic FXI inhibitors. We believe that therapeutic inhibition of the FXI axis is a promising therapeutic strategy to combat pathological thrombus formation, in light of the strong antithrombotic efficacy and mild bleeding diathesis associated with FXI deficiency. The ultimate goal of this line of research is to establish valuable mechanistic information concerning FXI-platelet interactions and to provide further insight into the physiological role of FXI in normal hemostasis and pathologic coagulation.

描述（由申请人提供）：凝血因子 XI (FXI) 水平升高是深静脉血栓形成、缺血性中风和心肌梗死的独立危险因素。遗传性 FXI 缺陷会导致轻度出血倾向，但它也被发现可以预防缺血性中风。 FXI 已被证明在实验性血栓形成中发挥着关键作用，FXI 的基因缺失或药理学抑制可防止动物血栓形成模型中的血管闭塞这一事实证明了这一点。虽然这些发现表明 FXI 在血栓形成中发挥重要作用，并且可能在止血中发挥作用，但它们并没有表明 FXI 对（病理）生理凝血有不同贡献的分子机制。血小板是初级止血的重要细胞成分。 FXI 已被证明可通过血小板糖蛋白 (GP) Ib-IX-V 复合物与血小板表面特异性结合；然而，这种相互作用的功能意义尚不清楚。此外，尚不清楚血流引起的剪切力是否在调节 FXI-血小板结合中发挥作用。有人认为 GPIb 通过蛋白酶凝血酶协调 FXI 的激活；然而，围绕这一假设存在相当大的争议。此外，虽然凝血酶、活化的 FXI (FXIa) 或活化的因子 XII (FXIIa) 已被证明可以在体外纯化系统中激活 FXI，但这些 FXI 激活剂在离体或体内血小板表面上的相对重要性尚未得到证实。已确立的。我们提出的研究的目的是阐明 FXI-血小板相互作用的机制，并进一步了解 FXI 在正常止血和病理性凝血中的生理作用。我们假设 FXI-血小板相互作用在剪切流条件下促进凝块形成。我们已确定 FXI 是血小板载脂蛋白 E 受体 2 (ApoER2) 的配体。我们假设 ApoER2 在介导 FXI-血小板结合和启动血流凝血中发挥关键作用。这些假设将通过以下具体目标进行检验：目标 1：确定血小板-FXI 相互作用的分子机制和后果。目标 2：确定 FXI-血小板结合在离体血栓形成中的作用。目标 3：确定 FXI-血小板结合在体内血栓形成中的作用。我们致力于新型抗血栓FXI抑制剂的设计和开发。鉴于与 FXI 缺乏相关的强大抗血栓功效和轻度出血素质，我们相信治疗性抑制 FXI 轴是对抗病理性血栓形成的一种有前途的治疗策略。这一系列研究的最终目标是建立有关 FXI-血小板相互作用的有价值的机制信息，并进一步了解 FXI 在正常止血和病理性凝血中的生理作用。