This application for a Mentored Clinical Scientist Development Award will investigate the development of mitochondrial dysfunction in late stage hemorrhagic shock and the potential benefit of vasopressin during resuscitation. The proposed research complements the mentors' biochemical, clinical and translational expertise and incorporates a formal education plan to complete a PhD in Biochemistry and Biophysics. PROJECT SUMMARY: Multiple organ dysfunction (MOD) remains the most common cause of in- hospital morbidity and mortality following traumatic injury. The underlying cellular events leading to MOD following hemorrhagic shock are uncertain, but impaired mitochondrial function has been strongly implicated. Recently, the hormone arginine vasopressin (AVP) has been investigated as an adjunct during the resuscitation of severe trauma. In addition to its vasopressor qualities, AVP may be important in thwarting the development of MOD following trauma by modulating the formation of NADH, activating mitochondrial ATP synthesis and inhibiting apoptosis. Based on preliminary data, we hypothesize that hemorrhagic shock results in modifiable defects in mitochondrial function that can be mitigated by supplementing AVP during resuscitation. This hypothesis will be tested in vivo using a naturally occurring AVP-knockout (i.e. Brattleboro rat) and ex-vivo using tissue samples from injured trauma patients. This unique translational approach seeks to understand how cellular pathways influence biological systems and ultimately impact the care of the trauma patient. Specifically, this research proposal will: 1) investigate the mechanism by which AVP provides mitochondrial protection (e.g. via Ca2+ signaling vs. kinase mediated complex subunit hyperphosphorylation), 2) determine if AVP supplementation during resuscitation decreases organ dysfunction, and 3) assess the impact of AVP on the mitochondrial function in tissue samples from severely injured patient. In addition to traditional techniques used to assess mitochondrial function, our use of Blue Native polyacrylamide electrophoresis provides an unprecedented opportunity to explore the mitochondrial proteome and post- translational modifications following shock. The proposed project is innovative because although AVP has been used as a vasopressor during resuscitation, its beneficial impact on mitochondrial metabolism has only been explored in vitro. Moreover, rigorous scientific validation supporting the use AVP during resuscitation has the potential to dramatically alter routine clinical practice. PROJECT
The knowledge gained from this proposal will contribute to the development of innovative, life-saving resuscitative strategies by providing a deeper understanding of how shock-induced mitochondrial dysfunction progresses to MOD.
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