Mitochondrial DNA in the pathogenesis of post-injury coagulopathy

线粒体 DNA 在损伤后凝血病发病机制中的作用

• 批准号: 10454902
• 负责人: MATTHEW E KUTCHER
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454902
• 关键词: Address; Advisory Committees; Agonist; Animal Model; Animals; Antifibrinolytic Agents; Award; Bilateral; Biological Assay; Biological Markers; Biology; Blood Coagulation Disorders; Blood Platelets; Cause of Death; Cessation of life; Clinical; Clinical Research; Coagulation Process; Cohort Studies; Complex; Critical Illness; Cytoplasmic Granules; DNA Damage; Data; Deoxyribonucleases; Development; Disease; Endothelial Cells; Exhibits; Extramural Activities; Feedback; Fibrinolysis; Foundations; Functional disorder; Funding; Goals; Hemorrhage; Hindlimb; Human; Immune; Impairment; In Vitro; Inflammation; Injury; Intervention; Intravenous; Knowledge; Length of Stay; Mediating; Mediator of activation protein; Medical center; Mentored Clinical Scientist Development Award (K08); Mentors; Mentorship; Metformin; Mississippi; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Multiple Organ Failure; Observational Study; Operative Surgical Procedures; Organ failure; Orthopedics; Outcome; Pathogenesis; Patients; Pattern; Pharmacology; Phenotype; Physiology; Plasma; Platelet Activation; Play; Prevalence; Refractory; Research; Research Personnel; Rest; Resuscitation; Rodent; Rodent Model; Role; Scientist; Surgeon; Testing; Thrombosis; Training; Transfusion; Translating; Trauma; Trauma Research; Trauma patient; Universities; Work; arm; base; career; clinical practice; design; experience; functional disability; human study; improved; improved outcome; inhibitor; injured; insight; interest; mortality; new therapeutic target; novel; novel therapeutics; platelet function; platelet phenotype; pre-clinical; prospective; response to injury; severe injury; skills; targeted treatment; translational approach; translational pipeline; translational study; trauma induced coagulopathy

PROJECT SUMMARY/ABSTRACT This application is for a K08 Mentored Clinical Scientist Development Award for Dr. Matthew Kutcher, a trauma surgeon and surgical intensivist at the University of Mississippi Medical Center. Dr. Kutcher is establishing himself as an early career investigator in translational trauma research, with a specific interest in the role of circulating mitochondrial DNA (mtDNA) as a driver of trauma-induced coagulopathy. This proposed K08 award will accomplish the following goals: (1) provide specific training and mentorship in mitochondrial, platelet, and fibrinolytic biology; (2) apply these newly-acquired skills and expertise to a translational study of mtDNA as a driver of trauma-induced coagulopathy, including clinical, mechanistic, and animal model arms; and (3) use these scientifically and clinically meaningful studies to facilitate independent funding supporting a career as a mature clinician-scientist. To accomplish these goals, Dr. Kutcher will be mentored by a Scientific Advisory Committee comprised of content experts and tested mentors. The Committee will be led by Dr. Robert Hester, a key institutional mentor of Dr. Kutcher’s, and includes leaders in the fields of mitochondrial physiology (Dr. Mark Gillespie and Dr. Jonathan Hosler) and coagulation biology (Dr. Mitchell Cohen and Dr. Alan Jones). The Committee is designed to collectively span the translational spectrum from clinical observational studies (Drs. Cohen and Jones), to mechanistic studies (Drs. Gillespie and Hosler), to preclinical animal models (Dr. Hester) with a strong foundation of statistical support (Dr. William Hillegass). Strong professional development and mentorship for a lifelong career as a clinician-scientist will be provided by Drs. Cohen and Jones. This study is motivated by the prevalence and deleterious effects of platelet dysfunction as a key component of coagulation abnormalities after injury, for which mechanistic understanding is poor and pharmacologic therapies are lacking. The central hypothesis of this proposal is that injury-induced release of mtDNA leads to mtDNA-mediated platelet activation, resulting in functionally impaired circulating platelets and inhibition of systemic fibrinolysis. Although precedent exists for the importance of mtDNA as a key effector of coagulopathy in clinical observational studies of trauma and in mechanistic and animal models of other disease states, mtDNA-mediated effects on platelets have not been studied in trauma. Using a truly translational approach, this proposal will examine a core set of key platelet and fibrinolytic functional assays, as applied to a prospective human study arm to gain key clinical insights (AIM 1), an ex vivo study arm in which to probe mechanisms (AIM 2), and an animal study in which to replicate human findings and evaluate potential interventions (AIM 3). These studies will address a critical knowledge gap in our understanding of trauma-induced coagulopathy, and identify specific mechanisms and novel therapeutic targets that will form the basis for a compelling R01 proposal focused on translating these findings into mitochondrial-targeted therapies to improve our resuscitation of critically injured patients.

项目总结/摘要 此应用程序是K 08指导临床科学家发展奖博士马修库彻，创伤 他是密西西比大学医学中心的外科医生和外科重症监护医师。库彻医生正在建立 他本人是翻译创伤研究的早期职业调查员，对翻译创伤的作用特别感兴趣。 循环线粒体DNA（mtDNA）作为创伤诱导的凝血病的驱动因素。此次K 08奖 将实现以下目标：（1）提供线粒体，血小板， 纤维蛋白溶解生物学;（2）将这些新获得的技能和专业知识应用于mtDNA的翻译研究， 创伤诱导的凝血障碍的驱动因素，包括临床、机械和动物模型组;和（3）使用这些 科学和临床上有意义的研究，以促进独立的资金支持职业生涯作为一个成熟的 临床科学家为了实现这些目标，库彻博士将接受科学咨询委员会的指导。 由内容专家和经过测试的导师组成。该委员会将由罗伯特·赫斯特博士领导， 库彻博士的机构导师，包括线粒体生理学领域的领导者（马克博士 吉莱斯皮和乔纳森·霍斯勒博士）和凝血生物学（米切尔·科恩博士和艾伦·琼斯博士）。的 委员会旨在共同跨越临床观察性研究（Drs. Cohen和Jones）、机制研究（吉莱斯皮博士和Hosler）、临床前动物模型（Hester博士） 有着坚实的统计学基础（威廉·希莱加斯博士）。强大的专业发展和 科恩博士和琼斯博士将为作为临床科学家的终身职业提供指导。本研究 血小板功能障碍作为凝血的关键成分， 损伤后的异常，其机制的理解是穷人和缺乏药物治疗。 这一建议的中心假设是损伤诱导的mtDNA释放导致mtDNA介导的血小板聚集。 活化，导致功能受损的循环血小板和抑制全身纤维蛋白溶解。虽然 在临床观察性研究中，mtDNA作为凝血障碍的关键效应物的重要性已有先例 在创伤和其他疾病状态的机制和动物模型中，mtDNA介导的对血小板的作用 还没有在创伤中进行过研究。使用真正的翻译方法，本提案将审查一套核心的 关键的血小板和纤溶功能测定，应用于前瞻性人类研究组，以获得关键的临床 洞察力（AIM 1），一个离体研究臂，其中探测机制（AIM 2），和动物研究，其中 复制人类的发现并评估潜在的干预措施（AIM 3）。这些研究将解决一个关键的 我们对创伤引起的凝血功能障碍的理解存在知识差距，并确定具体机制， 新的治疗目标，将形成一个引人注目的R 01提案的基础，重点是翻译这些 研究结果用于脑靶向治疗，以改善我们对严重受伤患者的复苏。