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: 10040301
• 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/10040301
• 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; Failure; 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; 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/antagonist; 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

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.

项目摘要/摘要 此申请表是为创伤医生Matthew Kutcher博士颁发的K08指导临床科学家发展奖 密西西比大学医学中心的外科医生和外科强化师。库彻博士正在建立 作为翻译创伤研究的早期职业研究员，他对以下角色特别感兴趣 循环线粒体DNA(MtDNA)是创伤所致凝血障碍的驱动因素。此建议的K08奖 将实现以下目标：(1)提供线粒体、血小板和 纤溶生物学；(2)将这些新获得的技能和专业知识应用于线粒体DNA的翻译研究 创伤性凝血障碍的驱动因素，包括临床、机械和动物模型武器；以及(3)使用这些 科学和临床上有意义的研究，以促进独立资助，支持职业生涯的成熟 临床医生兼科学家。为了实现这些目标，库彻博士将接受一个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·海丝特博士领导，他是 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)。这个 委员会旨在共同跨越临床观察性研究(Dr. 科恩和琼斯)，机械学研究(吉莱斯皮和霍斯勒博士)，临床前动物模型(海斯特博士) 具有强大的统计支持基础(威廉·希勒加斯博士)。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生涯提供指导。这项研究是 受到作为凝血关键成分的血小板功能障碍的流行和有害影响的推动 损伤后的异常，对其机理认识较差，缺乏药物治疗。 这一提议的中心假设是损伤诱导的mtDNA释放导致mtDNA介导的血小板。 激活，导致循环中的血小板功能受损，抑制全身纤溶。虽然 在临床观察研究中，线粒体DNA作为凝血障碍的关键效应因子的重要性是有先例的 在创伤和其他疾病状态的机械性和动物模型中，线粒体DNA对血小板的影响 还没有在外伤学中进行过研究。使用真正的翻译方法，该提案将检查一组核心的 关键的血小板和纤溶功能分析，应用于一项预期的人体研究，以获得关键的临床 洞察力(目标1)，用于探索机制的体外研究臂(目标2)，以及用于 复制人类的发现并评估可能的干预措施(目标3)。这些研究将解决一个关键的 在我们对创伤引起的凝血障碍的理解方面的知识差距，并确定具体的机制和 新的治疗目标，将形成一个引人注目的R01提案的基础，专注于翻译这些 线粒体靶向治疗的发现，以改善我们对危重损伤患者的复苏。