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

• 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
• 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

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疗法将是一种变革性的进步 管理数百万患有心肌梗塞，血栓栓塞疾病和 需要抗凝剂，但有目前可用的药物有大量出血的风险。 一个高度有希望的目标是凝血因子XII（FXII/FXIIA），这是基于最近缺乏小鼠的发现 FXII受到明显的保护，免于血栓形成，而不会增加出血。因为长期以来已经知道 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 开创性的抗血栓形成靶标，可以从出血并发症中“解除”有效性。作为证明 概念，我们已经表明X210-C01是一种针对鼠FXIIA的新型治疗抗体，可防止动脉 在保存止血的同时，小鼠的血栓形成。但是，招募FXII的机制， 激活并在动脉血栓形成期间传播，但止血尚未吸引。我们的 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 通过血浆辅因子的阳性反馈来扩增哪些FXIIA。定义分子机制 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 血栓形成中FXIIA的必需辅助因子。我们将使用一种新型的抗PK抗体（M202-H03） 评估双PK和FXIIA封锁对体内血栓形成的影响。我们还将研究 PK与FXII相互作用并激活FXII的机制。 2）定义FXII激活的机制 体内血栓形成。我们将测试磷脂酰丝氨酸和血小板GPIBα是否需要 足以激活血小板表面的FXII。然后，我们将使用插入性共聚焦显微镜定位FXII 3）使用体内模型，测试FXII抑制是否会损害止血和 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博士非常有资格执行拟议的实验。他是 致力于从事止血和血栓形成方面的科学职业，并提出了全面的 五年计划实现他成为独立身体科学家的目标。 Bendapudi博士将工作 在罗伯特·弗拉曼哈夫特（Robert Flaumenhaft）博士的主要心态下，布鲁斯·弗里（Bruce Furie）博士担任联合学。他有 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。 贝丝以色列执事中心的止血和血栓形成是理想的环境 鉴于其杰出的研究社区，他的科学和职业发展目标 以及该领域的科学发现和学员心态的传统。