Traumatic injury is predicted to exceed communicable disease in the year 2020 as the number one cause of disability-adjusted-life-years worldwide. Every trauma surgeon is intimately aware of the intense frustration of fighting to obtain an operative cure, only to watch the patient succumb to the poorly understood pathophysiologic sequelae of trauma. Among these poorly understood sequelae are the endothelial dysfunction and massive microvascular leak that increase morbidity and mortality in trauma patients. The proposed research will investigate the lipid metabolism that determines the endothelial dysfunction and microvascular fluid leak after injury by using an ischemia-reperfusion model as a surrogate to trauma. The hypothesis is that lysophosphatidic acid (LPA) controls post-injury microvascular fluid leak. My interlocking Specific Aims are: 1) To determine whether LPA production following mesenteric ischemia-reperfusion provokes microvascular leak, 2) To relate microvascular endothelial phosphatidylserine (PS) exposure to the production of LPA following mesenteric ischemia- reperfusion, and 3) To knockdown phospholipid scramblase 1 (PLSCR1), the protein that mobilizes phosphatidylserine (PS) to the outer endothelial cell membrane, by RNA interference (RNAi).
These specific aims will be accomplished through a multi-faceted investigation using RNA interference, molecular biology, immunohistochemistry, biochemistry and physiology assays. These experiments will improve our understanding of the dysregulation of lipid metabolism after injury and could ultimately lead to new treatments for trauma patients. This career development research proposal sets forth a strategic plan that incorporates coursework in biochemistry, molecular and cell biology at DC Berkeley and mentored laboratory training in lipid biochemistry by Dr Kuypers at CHORI and in molecular biology by Dr Bhargava at UCSF. Dr Harken, a surgical leader in this country, will oversee my development as a clinician-scientist. I will also receive guidance from Dr Twomey, Emeritus Professor and expert in medical editing and biostatistics, which will help me improve my ability to communicate with other scientists.
