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 创伤后的凝结概况的改变与静脉血栓栓塞事件有关 创伤性脑损伤后随后发病。血小板超凝结和微粒产生 在这种正在进行的凝血病的发展中发挥作用。酸鞘磷脂酶活性可能有助于 均为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的时间依赖性变化，酸鞘磷脂酶 活性，神经酰胺的浓度以及随后的高凝血小板来源的生成 微粒。该提案的总体目标是证明酸鞘磷脂酶的变化 活性改变了血小板功能和微颗粒的产生，导致高凝性和 创伤性脑损伤后血栓栓塞风险，以下目的：目标1：阐明酸 在 创伤性脑损伤。目标2：确定酸鞘磷脂酶在调节血小板衍生的作用 通过创伤释放的促炎因子刺激后的微粒生成和功能 脑损伤。 AIM 3：确定酸鞘磷脂酶的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。这些目标成功完成 可能导致新的疗法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