Regulation of endothelial cell phosphatidylserine in thrombosis

血栓形成中内皮细胞磷脂酰丝氨酸的调节

基本信息

项目摘要

Project Summary/Abstract A prothrombotic vessel wall is implicated as a major driver of cardiovascular disease, including heart attacks, strokes, and venous thromboembolism. Despite extensive research into the mechanisms of endothelial cell dysfunction, the fundamental question of how a clot forms in blood vessels remains incompletely understood. Activation of blood coagulation enzymes requires a membrane surface containing anionic phospholipids, most notably phosphatidylserine (PS). PS-binding proteins decrease thrombosis in animal models suggesting that targeting PS exposure may be a novel antithrombotic strategy. Plasma membrane PS is normally sequestered on the inner membrane leaflet. To activate blood coagulation, PS must be externalized to the outside of the cell by calcium-activated phospholipid scramblases. Platelets readily externalize PS in vitro, and it has often been assumed, but not clearly demonstrated, that platelets generate the procoagulant PS to promote thrombosis in vivo. Our data demonstrate that (1) the majority of PS externalization in vivo actually derives from the vessel wall, independent of platelets, and (2) inhibiting TMEM16 phospholipid scramblases decreases the thrombotic potential of the vessel wall. We have identified two TMEM16 family members, TMEM16F, and its closest paralog TMEM16E, that are both required for PS externalization and procoagulant activity in endothelial cells. TMEM16E is not found in platelets and previously has no known role in coagulation. The central hypothesis of this application is that the endothelial cell membrane is the primary source of PS in forming a thrombus, and its externalization is regulated by two scramblases, TMEM16E and TMEM16F. In Aim 1 we will determine the mechanism by which both TMEM16E and TMEM16F promote PS externalization and procoagulant activity in endothelial cells. In Aim 2 we will use mouse models and intravital microscopy to determine the contribution of endothelial cell-derived PS to thrombosis and how it is regulated by TMEM16E and TMEM16F in vivo. This proposal describes a five-year research training program for Dr. Alec Schmaier’s mentored career development. The applicant has a strong research background in platelet activation from the Medical Scientist Training Program at the University of Pennsylvania. This proposal expands his skill set through investigations in endothelial cell biology, blood coagulation and vessel wall thrombosis. Dr. Robert Flaumenhaft in the Division of Hemostasis and Thrombosis at Beth Israel Deaconess Medical Center will be the primary research mentor. Dr. Flaumenhaft has a distinguished record of mentorship and innovation in thrombosis research. In addition, the applicant’s advisory committee will provide highly relevant scientific expertise and critical assessment of his progress. In sum, Dr. Schmaier has created an outstanding environment to advance his research and career goals to be a physician-scientist in cardiovascular medicine. This comprehensive training program will position him to succeed as an independent investigator in thrombosis and vascular biology.
项目摘要/摘要 血栓前血管壁被认为是包括心脏病发作在内的心血管疾病的主要驱动因素, 中风和静脉血栓栓塞症。尽管对内皮细胞的机制进行了广泛的研究 功能障碍,血栓如何在血管中形成的根本问题仍然没有完全被了解。 激活凝血酶需要膜表面含有阴离子磷脂,大多数 特别是磷脂酰丝氨酸(PS)。PS结合蛋白减少动物模型血栓形成提示 靶向PS暴露可能是一种新的抗血栓策略。质膜PS通常被隔离 在内膜传单上。为了激活血液凝固,PS必须外化到细胞的外部 被钙激活的磷脂扰乱酶激活。在体外,血小板很容易使PS外化,而且它经常被 假设,但没有清楚地证明,血小板产生促凝剂PS以促进血栓形成 活着。我们的数据表明:(1)体内PS的大部分外化实际上来自血管 和(2)抑制TMEM16磷脂扰乱酶可减少血栓形成 脉管壁的潜力。我们已经确定了两个TMEM16家族成员TMEM16F及其最接近的成员 PARALLOG TMEM16E,这是PS外化和内皮细胞促凝血活性所必需的。 TMEM16E在血小板中没有发现,以前也没有已知的凝血作用。的中心假说 这一应用是内皮细胞膜是形成血栓的PS的主要来源,其 外化受两个加扰酶TMEM16E和TMEM16F的调控。在目标1中,我们将确定 TMEM16E和TMEM16F促进PS外化和促凝活性的机制 内皮细胞。在目标2中,我们将使用小鼠模型和活体显微镜来确定 内皮细胞来源的PS对血栓形成的影响以及TMEM16E和TMEM16F如何在体内调节它。 这份提案描述了Alec Schmaier博士指导职业生涯的五年研究培训计划 发展。申请者具有医学科学家在血小板活化方面的强大研究背景 宾夕法尼亚大学的培训计划。这项建议通过调查扩大了他的技能范围 在内皮细胞生物学中,凝血和血管壁血栓形成。罗伯特·弗劳门哈夫特博士在 贝丝以色列女执事医疗中心的止血和血栓科将是主要研究 门托。Flaumenhaft博士在血栓研究方面有着卓越的指导和创新记录。在……里面 此外,申请人的咨询委员会将提供高度相关的科学专业知识和关键 对他进步的评估。总而言之,施迈尔博士创造了一个出色的环境来推进他的 研究和职业目标是成为心血管内科的内科科学家。这次综合培训 该计划将使他成为血栓形成和血管生物学领域的独立研究员。

项目成果

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Alec Andrew Schmaier其他文献

Alec Andrew Schmaier的其他文献

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{{ truncateString('Alec Andrew Schmaier', 18)}}的其他基金

Regulation of endothelial cell phosphatidylserine in thrombosis
血栓形成中内皮细胞磷脂酰丝氨酸的调节
  • 批准号:
    10541214
  • 财政年份:
    2022
  • 资助金额:
    $ 16.47万
  • 项目类别:

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