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

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM097614-03
Application #
8494641
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$126,576
Indirect Cost
$9,376
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Wang, Hao; Guan, Yuxia; Karamercan, Mehmet Akif et al. (2015) Resveratrol Rescues Kidney Mitochondrial Function Following Hemorrhagic Shock. Shock 44:173-80
Morris, David S; Rohrbach, Jeff; Sundaram, Latha Mary Thanka et al. (2014) Early hospital readmission in the trauma population: are the risk factors different? Injury 45:56-60
Wang, Hao; Guan, Yuxia; Widlund, Anne Lykkegaard et al. (2014) Resveratrol ameliorates mitochondrial dysfunction but increases the risk of hypoglycemia following hemorrhagic shock. J Trauma Acute Care Surg 77:926-33
Perales Villarroel, José Paul; Figueredo, Ronald; Guan, Yuxia et al. (2013) Increased platelet storage time is associated with mitochondrial dysfunction and impaired platelet function. J Surg Res 184:422-9
Karamercan, Mehmet Akif; Weiss, Scott L; Villarroel, Jose Paul Perales et al. (2013) Can Peripheral Blood Mononuclear Cells be Used as a Proxy for Mitochondrial Dysfunction in Vital Organs During Hemorrhagic Shock and Resuscitation? Shock :
Sims, Carrie A; Isserman, Joshua A; Holena, Daniel et al. (2013) Exception from informed consent for emergency research: consulting the trauma community. J Trauma Acute Care Surg 74:157-65; discussion 165-6
Villarroel, Jose Paul Perales; Guan, Yuxia; Werlin, Evan et al. (2013) Hemorrhagic shock and resuscitation are associated with peripheral blood mononuclear cell mitochondrial dysfunction and immunosuppression. J Trauma Acute Care Surg 75:24-31
Grill, Elena; Strong, Michelle; Sonnad, Seema S et al. (2013) Altered thyroid function in severely injured patients. J Surg Res 179:132-7
Georgoff, Patrick; Perales, Paul; Laguna, Benjamin et al. (2013) Colonic injuries and the damage control abdomen: does management strategy matter? J Surg Res 181:293-9

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