The Role of Coagulation Factor XII in Hemostasis and Thrombosis

凝血因子 XII 在止血和血栓形成中的作用

基本信息

批准号：
9294310
负责人：
Pavan Bendapudi
金额：
$ 16.34万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294310
关键词：
Address Advisory Committees Antibodies Anticoagulation Binding Biology Blood Platelets Blood Vessels Clinical Coagulation Process Communities Confocal Microscopy Custom Disease Disease susceptibility Dose Endothelium Environment Factor XII Factor XII Deficiency Feedback Fibrin Five-Year Plans Generations Goals Hematology Hemorrhage Hemostatic Agents Hemostatic function Human Impairment In Vitro Injury International Israel Laser injury Maps Mechanics Mediating Medical center Mentors Mentorship Modeling Molecular Monitor Mus Myocardial Infarction Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphatidylserines Phospholipids Physicians Physiological Plasma Plasma Kallikrein Platelet Activating Factor Play Process Proteins Reagent Recruitment Activity Research Risk Role Scientist Serine Protease Site Stroke Surface System Testing Therapeutic antibodies Thrombin Thrombosis Thrombus Treatment Efficacy Veins Wild Type Mouse Work base career career development cofactor experimental study in vitro Assay in vivo in vivo Model innovation insight mouse model novel novel strategies novel therapeutics prevent receptor synergism

项目摘要

Project Summary/Abstract Discovery of an antithrombotic therapy that does not cause bleeding would be a transformative advance in the management of millions of patients with conditions such as myocardial infarction, thromboembolic disease, and stroke who require anticoagulation but are put at risk of major hemorrhage with currently available medications. One highly promising target is coagulation factor XII (FXII/FXIIa), based on the recent finding that mice lacking FXII are strikingly protected from thrombosis without increased bleeding. Because it has long been known that severe congenital FXII deficiency in humans does not cause bleeding, these results make FXII a potentially groundbreaking antithrombotic target that could “decouple” efficacy from bleeding complications. As proof of concept, we have shown that X210-C01, a novel therapeutic antibody against murine FXIIa, prevents arterial thrombus formation in mice while preserving hemostasis. However, the mechanism by which FXII is recruited, activated, and propagated during arterial thrombosis but not hemostasis remains poorly understood. Our central hypothesis is that platelets bind and activate FXII in arterial thrombi but not in hemostatic plugs, after which FXIIa is amplified by positive feedback via a plasma cofactor. To define the molecular mechanisms underlying FXII function in vivo, we propose the following aims: 1) Test whether plasma kallikrein (PK) is an essential cofactor for FXIIa in thrombus formation. We will use a novel anti-PK antibody (M202-H03) to evaluate the effect of dual PK and FXIIa blockade on thrombus formation in vivo. We will also study the mechanism by which PK interacts with and activates FXII. 2) Define mechanisms of FXII activation during thrombus formation in vivo. We will test whether phosphatidylserine and platelet GPIbα are necessary and sufficient to activate FXII at the platelet surface. We will then use intravital confocal microscopy to localize FXII during thrombus formation. 3) Using in vivo models, test whether FXII inhibition impairs hemostasis and determine if platelets in hemostatic plugs are phenotypically distinct from those in arterial thrombi. The applicant, Dr. Pavan Bendapudi, is well qualified to execute the proposed experiments. He is committed to pursuing a scientific career in hemostasis and thrombosis and has proposed a comprehensive five-year plan to meet his goal of becoming an independent physician-scientist. Dr. Bendapudi will be working under the primary mentorship of Dr. Robert Flaumenhaft with Dr. Bruce Furie serving as co-mentor. He has enlisted a research advisory committee of internationally-recognized experts in hematology to support him. The Division of Hemostasis and Thrombosis at Beth Israel Deaconess Medical Center is an ideal environment for completion of his scientific and career development objectives given its outstanding research community and tradition of scientific discovery and trainee mentorship in this field.

项目摘要/摘要发现不引起出血的抗血栓形成疗法将是一个变革性的进步管理数百万患有心肌梗塞，血栓栓塞疾病等疾病的患者需要抗凝但有目前可用药物的大量出血风险的中风。一个高度有希望的目标是凝血因子XII（FXII/FXIIIA），这是基于最近缺乏小鼠的发现 FXII受到严格保护，免于血栓形成，并增加出血。人类严重的先天性FXII缺乏并不会引起出血，这些结果可能使FXII成为可能突破性的抗血栓形成靶标可以“脱离”出血并发症的功效。概念，我们已经表明，X210-C01是一种针对鼠的新型世代抗体，可防止动脉在保存止血的同时，小鼠的血栓形成。激活，在动脉血栓形成期间传播，但止血尚不清楚。中心假设是血小板在动脉血栓中结合并激活FXII，但在止血塞中不结合并激活FXII FXIIA通过血浆辅助因子放大，以定义分子机理。在体内的基础FXII功能，我们提出以下目的：1）测试血浆Kallikrein（PK）是否是 FXIIA的必需辅助因子在血栓形成中。评估双PK和FXIIA封锁对体内血栓形成的影响。 PK与FXII相互作用并激活FXII的机制。血栓形成在体内。足以在血小板表面激活FXII。在血栓形成期间。3）使用体内模型，测试FXII抑制是否会损害止血确定止血塞中的血小板是否在表型上与动脉血栓中的血小板不同。申请人Pavan Bendapudi博士有资格执行他的实验致力于从事止血和Thombosis的科学职业，并提出了全面的五年计划实现了他的目标是独立医师科学家的目标。在罗伯特·弗劳曼哈夫特（Robert Flaumenhaft）博士的主要指导下，布鲁斯·弗里（Bruce Furie）担任联合学。招募了一个国际认可的血液学专家研究咨询委员会，以支持他。止血和血栓形成在血栓形成时的划分下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注赌注下注赌注下注赌注下注赌注下注赌注下注赌注下注赌注赌注贝特为了压缩他的科学和职业发展目标，鉴于出色的研究社区以及该领域的科学发现和实习指导的传统。