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
- 批准号:10348804
- 负责人:
- 金额:$ 16.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdvisory CommitteesAffectAnimal ModelAnimalsApoptosisBinding ProteinsBiologicalBiologyBleeding time procedureBloodBlood PlateletsBlood VesselsBlood coagulationCalciumCardiovascular DiseasesCardiovascular systemCell membraneCell surfaceCellsCellular biologyChildhoodCoagulation ProcessDataDevelopmentEndothelial CellsEndotheliumEnvironmentEnzymesExposure toFamilyFamily memberFibrinFunctional disorderGenerationsGoalsHemostatic functionIn VitroInflammationInjuryInvestigationIsraelKnockout MiceLaser injuryLasersLipidsMedicalMedical centerMedicineMembraneMentorsMentorshipMicroscopyModelingMultienzyme ComplexesMuscular DystrophiesMutationMyocardial InfarctionOutcomeParticipantPathologicPennsylvaniaPhosphatidylserinesPhospholipidsPhysiciansPhysiologicalPlatelet ActivationPositioning AttributeProcessReactionRegulationResearchResearch PersonnelResearch TrainingRoleScientistSiteSkeletal MuscleSourceStrokeSumSurfaceTechniquesTestingThromboplastinThrombosisThrombusTraining ProgramsUniversitiesVascular EndotheliumWorkbasebonecareercareer developmentcofactordefined contributionendothelial cell procoagulant activityfactor IXa-factor VIIIaferric chloridehuman diseasein vitro Modelin vivoin vivo Modelinhibitorinnovationintravital microscopyloss of function mutationmouse modelnovelnovel therapeuticsparalogous genephospholipid scramblaseskillsthromboticvenous thromboembolism
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.
项目总结/摘要
血栓前血管壁是心血管疾病的主要驱动因素,包括心脏病发作,
中风和静脉血栓栓塞尽管对内皮细胞的机制进行了广泛的研究,
然而,对于血栓如何在血管中形成的基本问题,仍然没有完全理解。
凝血酶的激活需要含有阴离子磷脂的膜表面,大多数
特别是磷脂酰丝氨酸(PS)。PS结合蛋白减少动物模型中的血栓形成,表明
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
在内膜瓣叶上。要激活血液凝固,PS必须外化到细胞外
由钙激活的磷脂乱序酶引起血小板在体外很容易使PS外化,
假设,但没有明确证明,血小板产生促凝血PS,以促进血栓形成,
vivo.我们的数据表明:(1)体内PS外化的大部分实际上来自血管
(2)抑制TMEM 16磷脂乱序酶可降低血栓形成,
血管壁的电位。我们已经确定了两个TMEM 16家族成员,TMEM 16 F,以及它最接近的成员。
paraeTMEM 16 E,其是内皮细胞中PS外化和促凝血活性所需的。
TMEM 16 E在血小板中未发现,并且先前在凝血中没有已知的作用。的中心假设
这种应用是内皮细胞膜是形成血栓的PS的主要来源,
外化由两种乱序酶TMEM 16 E和TMEM 16 F调节。在目标1中,我们将确定
TMEM 16 E和TMEM 16 F促进PS外化和促凝血活性的机制
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它如何在体内被TMEM 16 E和TMEM 16 F调节。
该提案描述了一个为期五年的研究培训计划博士亚历克施迈尔的指导职业生涯
发展申请人在医学科学家处拥有强大的血小板活化研究背景
宾夕法尼亚大学的培训课程。这项提议通过调查扩大了他的技能
内皮细胞生物学、血液凝固和血管壁血栓形成。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形成部门将是主要研究
导师Flaumenhaft博士在血栓形成研究方面有着杰出的指导和创新记录。在
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的
评估他的进步。总之,Schmaier博士创造了一个出色的环境,
研究和职业目标是成为心血管医学的医生科学家。这种全面的训练
该计划将使他成为血栓形成和血管生物学的独立研究者。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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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