The proposal entails a three-year training program focused on preparing the principle investigator (PI) for an independent career as a surgeon-scientist in the field of diabetic peripheral arterial disease. The PI previously earned a PhD in Pharmacology and obtained additional training in translational cardiovascular research. He is currently an Assistant Professor in the Department of Surgery, Section of Vascular Surgery, at Washington University. The project and career development plan aim to impart skills and knowledge required for the applicant to achieve his long-term goals of contributing insights into the role of phospholipid synthesis (phospholipogenesis) and endothelial cell (EC) lipidomics in peripheral arterial pathology in the setting of diabetes. The immediate training objectives of the PI are to master critical experimental techniques, complete coursework that will expand his understanding of lipid metabolism and drug development, develop administrative skills necessary for later autonomy, and produce a body of scientific work that will facilitate funding as an independent surgeon-scientist. Dr. Clay Semenkovich, Chief of Endocrinology, Metabolism, and Lipid Research at Washington University, and a carefully selected panel of career development committee members, will mentor and provide the resources necessary to achieve his goals for transition to independence. Project Summary: Diabetic peripheral arterial disease (PAD) is a highly prevalent disease process with significant morbidity that leads to stubbornly high rates of wounds, infections, and major extremity amputations. Previous studies demonstrate that in the setting of diabetes there is decreased arterial collateral development and significantly altered tissue-specific phospholipid expression (phospholipogenesis). But due to lake of animal models, little is known regarding the role of phospholipogenesis in the vascular endothelium in the setting of diabetes. The PI has observed that choline-ethanolamine phosphotransferase-1 (CEPT1; the terminal enzyme required for the synthesis of the majority of mammalian phospholipids) has altered expression in the peripheral arterial intima in the setting of diabetes and advanced atherosclerotic disease. CEPT1 expression can also be manipulated in ECs with sulfhydryl reducing pharmacological agents. Pilot human studies also demonstrate that specific CEPT1-generated, arachidonic acid (AA)-containing, plasmenyl- phosphatidylethanolamine (pPE) have altered expression in the peripheral arterial intima of diabetic patients. The data suggests that CEPT1-mediated phospholipogenesis is dependent on specific disease states (i.e. diabetes and PAD) and can be potentially targeted pharmacologically. To test this hypothesis further the PI will evaluate the role of CEPT1 and phospholipiogenesis in EC function and arteriogenesis using a novel conditional, endothelium-specific, CEPT1 knockout mouse model. The PI will also evaluate whether CEPT1 can be pharmacologically targeted with sulfhydryl reducing agents, and determine whether the CEPT1-pPE-AA biosynthesis pathway is increased in human diabetic peripheral arterial intima. Understanding this novel mechanism in diabetic PAD would have broad implications that can result in the development of novel therapeutics for this highly vulnerable patient population.
This career development proposal has two important components that will benefit public health. The first is the development of the principal investigator into an independent surgeon-scientist, which is a uniquely trained surgeon who can both treat patients surgically, and also identify potential therapeutic modalities for patients who are otherwise not best served by traditional surgical techniques. The second is the identification of a previously unrecognized process of lipid production in cells of the peripheral arteries. Understanding this process and its impact on peripheral arterial tissue in the setting of diabetes may provide new and important therapeutic drug targets for these patients.
