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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：
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
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/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

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.

项目总结/文摘