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Role of acid sphingomyelinase in the modulation of coagulation after traumatic brain injury

酸性鞘磷脂酶在脑外伤后凝血调节中的作用

基本信息

批准号：
9908098
负责人：
Michael Goodman
金额：
$ 30.5万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908098
关键词：
Affect Arachidonic Acids Automobile Driving Blood Coagulation Disorders Blood Platelets Brain Concussion Cardiovascular Diseases Ceramides Cerebrum Clinical Closed head injuries Coagulation Process Craniocerebral Trauma Data Development Drops Endothelial Cells Endothelium Enzymes Etiology Event Functional disorder Generations Goals Incidence Inflammation Process Inflammatory Injury Lead Malignant Neoplasms Membrane Modeling Morbidity - disease rate Mus Organ Pathologic Patients Pharmacology Platelet Activation Platelet aggregation Play Production Regulation Risk Role Sphingomyelins Testing Thrombophilia Thromboplastin Thrombosis Thrombus Time Trauma Traumatic Brain Injury Venous Weight acid sphingomyelinase clinically significant disability insight mortality new therapeutic target novel novel therapeutics overexpression platelet function release factor response tool venous thromboembolism

项目摘要

Project Summary Alterations in the coagulation profile after trauma are associated with venous thromboembolic events and subsequent morbidity after traumatic brain injury. Platelet hyperaggregration and microparticle generation play a role in the development of this ongoing coagulopathy. Acid sphingomyelinase activity may contribute to both platelet function and microparticle production. Our preliminary data have demonstrated that traumatic brain injury results in time-dependent changes in platelet aggregation, acid sphingomyelinase activity, ceramide concentration, and subsequent generation of hypercoagulable platelet-derived microparticles.The overall goal of this proposal is to demonstrate that changes in acid sphingomyelinase activity alter platelet function and microparticle generation, leading to hypercoagulability and thromboembolic risk after traumatic brain injury, with the following aims: Aim 1: Elucidate acid sphingomyelinase-dependent factors driving arachidonic acid-induced changes in platelet function following traumatic brain injury. Aim 2: Determine the role of acid sphingomyelinase in modulating platelet-derived microparticle generation and function after stimulation by proinflammatory factors released by traumatic brain injury. Aim 3: Determine how acid sphingomyelinase activity regulates traumatic brain injury-induced platelet-derived microparticle and/or platelet endothelial activation. Successful completion of these aims may lead to novel therapies to reduce posttraumatic thromboembolic events.

项目概要创伤后凝血特征的改变与静脉血栓栓塞事件有关脑外伤后的后续发病率。血小板过度聚集和微粒生成在这种持续性凝血病的发展中发挥作用。酸性鞘磷脂酶活性可能有助于血小板功能和微粒产生。我们的初步数据表明创伤性脑损伤导致血小板聚集、酸性鞘磷脂酶的时间依赖性变化活性、神经酰胺浓度以及随后产生高凝血小板衍生的该提案的总体目标是证明酸性鞘磷脂酶的变化活性改变血小板功能和微粒生成，导致高凝状态和创伤性脑损伤后的血栓栓塞风险，目标如下：目标 1：阐明酸鞘磷脂酶依赖性因素驱动花生四烯酸诱导的血小板功能变化脑外伤。目标 2：确定酸性鞘磷脂酶在调节血小板衍生中的作用创伤释放的促炎因子刺激后微粒的产生和功能脑损伤。目标 3：确定酸性鞘磷脂酶活性如何调节创伤性脑损伤引起的血小板衍生的微粒和/或血小板内皮激活。顺利完成这些目标可能会导致减少创伤后血栓栓塞事件的新疗法。