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

• 批准号: 10396016
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396016
• 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

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.

项目摘要 创伤后凝血谱的改变与静脉血栓栓塞症和 创伤性脑损伤后的继发发病率。血小板超聚集与微粒生成 在这种持续的凝血障碍的发展中发挥作用。酸性鞘磷脂酶活性可能起到一定作用 对血小板功能和微粒产生都有影响。我们的初步数据表明， 脑创伤后血小板聚集、酸性鞘磷脂酶的时间依赖性变化 活性、神经酰胺浓度和随后产生的高凝血小板源 这项提议的总体目标是证明酸性鞘磷脂酶的变化 活动改变了血小板功能和微粒生成，导致高凝状态和 创伤性脑损伤后血栓栓塞症的风险，目的如下：目的1：阐明酸 神经鞘磷脂酶依赖因子驱动花生四烯酸诱导的血小板功能改变 创伤性脑损伤。目的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 脑部受伤。目的3：确定酸性鞘氨酸酶活性如何调节创伤性脑损伤 血小板衍生微粒和/或血小板内皮细胞激活。圆满完成这些目标 可能会导致新的治疗方法，以减少创伤后血栓栓塞事件。

项目成果

The Role of Acid Sphingomyelinase Inhibition in Repetitive Mild Traumatic Brain Injury.

• DOI: 10.1016/j.jss.2020.09.034
• 发表时间: 2021-03
• 期刊: The Journal of surgical research
• 作者: Niziolek GM;Hoehn RS;Seitz AP;Jernigan PL;Makley AT;Gulbins E;Edwards MJ;Goodman MD
• 通讯作者: Goodman MD

Acid Sphingomyelinase Inhibition Mitigates Histopathological and Behavioral Changes in a Murine Model of Traumatic Brain Injury.

酸性鞘磷脂酶抑制可减轻创伤性脑损伤小鼠模型的组织病理学和行为变化。

• DOI: 10.1089/neu.2019.6436
• 发表时间: 2020
• 期刊: Journal of neurotrauma
• 影响因子: 4.2
• 作者: Niziolek,GraceM;Boudreau,RyanM;Baker,Jennifer;Friend,LouAnn;Makley,AmyT;Edwards,MichaelJ;Gulbins,Erich;Goodman,MichaelD
• 通讯作者: Goodman,MichaelD