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

基本信息

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
项目类别：
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

项目摘要

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/摘要该申请是为Matthew Kutcher博士的K08指导的临床科学家发展奖，密西西比大学医学中心的外科医生和外科强化主义者。 Kutcher博士正在建立他本人是转化创伤研究的早期职业研究者，对循环线粒体DNA（mtDNA）是创伤诱导的凝血病的驱动器。该提议的K08奖将实现以下目标：（1）在线粒体，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MTDNA的翻译研究创伤引起的凝血病的驱动器，包括临床，机械和动物模型臂；（3）使用这些科学和临床上有意义的研究，以促进独立资金支持职业成熟的职业临床科学家。为了实现这些目标，Kutcher博士将由科学咨询委员会考虑包括内容专家和经过测试的导师。委员会将由钥匙Robert Hester博士领导 Kutcher博士的机构导师，包括线粒体生理学领域的领导者（Mark博士吉莱斯皮（Gillespie）和乔纳森·霍斯勒（Jonathan Hosler）博士）和凝结生物学（米切尔·科恩（Mitchell Cohen）和艾伦·琼斯（Alan Jones）博士）。这委员会旨在从临床检查研究（Drs。科恩和琼斯（Cohen and Jones），进行机械研究（吉莱斯皮（Gillespie）和霍斯勒（Hosler）博士），到临床前动物模型（Hester博士）以统计支持的强大基础（William Hillegass博士）。强大的专业发展和 Drs将提供临床科学家的终身职业生涯。科恩和琼斯。这项研究是由血小板功能障碍作为凝结的关键组成部分的流行和有害影响的动机受伤后的异常，机械理解不足，并且缺乏药理疗法。该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，导致功能受损的循环血小板并抑制全身纤维蛋白溶解。虽然在临床观察性研究中，MTDNA作为凝血病的关键效应的重要性存在先例在其他疾病状态的创伤以及动物模型中，mtDNA介导的对血小板的影响尚未研究创伤。该建议将使用真正翻译的方法检查钥匙血小板和纤维蛋白水解功能测定，应用于前瞻性人类研究部门，以获得关键的临床洞察力（AIM 1），一个探测机制的离体研究部门（AIM 2），以及动物研究复制人类发现并评估潜在的干预措施（AIM 3）。这些研究将解决关键我们对创伤引起的凝血病的理解中的知识差距，并确定特定机制和新型热目标将构成引人注目的R01提案的基础，该提案重点是翻译这些线粒体靶向疗法的发现，以改善我们对重伤患者的复苏。