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.
This study is motivated by the observation that platelets are frequently dysfunctional immediately following severe injury, a phenomenon which is associated with worse outcomes but which remains poorly understood and therefore inadequately treated. Based on observational studies of injured patients and mechanistic studies in other disease states, there is evidence that mitochondrial DNA released in response to injury acts directly on platelets, leading to platelet dysfunction and impaired systemic fibrinolysis. This proposal aims to evaluate the effect of mitochondrial DNA on platelets by examining a core set of platelet and fibrinolytic functional assays, as applied to an observational human study to gain key clinical insights, a study of isolated platelets in which to probe mechanisms, and an animal study in which to replicate human findings and evaluate potential therapies.
