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.