This application for Denis Glenn M.D.,Ph.D. describes a five year strategy designed to enhance his research and professional skills with the ultimate goal of transitioning to an independent, academic investigator in the field of renal and cardiovascular biology. The research proposal seeks to understand the role of the enzyme, diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the final step in triglyceride synthesis, in the heart. DGAT activity and expression have been shown to be increased in animal models of diabetes and ischemic heart disease. However, it remains unclear if enhanced DGAT1 activity and the resulting lipid accumulation in the heart are pathogenic. To begin to address this question a cardiac selective DGAT1 transgenic mouse has been created and preliminary results suggest that DGAT1 over expression results in cardiac dysfunction.
The first aim will define the role of neutral lipid deposition as a risk factor for the development of cardiac dysfunction in the cardiac DGAT1 transgenic mouse subjected to high fat diet and pharmacologically induced cardiac hypertrophy. Initial characterization of this mouse has revealed.a reduction in expression of the deacetylase SIRT1 and the second aim will explore the role of SIRT1 and PGC1 alpha in mediating the effects of lipid deposition and cardiac myocyte dysfunction. The mentored research and training plan will provide experience in development of mouse models of disease, advanced training in cardiovascular assessment in the mouse and professional skills development. The mentor. Dr. David Gardner is an expert in the field of cardiovascular and renal research and will continue to advise both scientifically and professionally. In addition, a scientific advisory and mentorship committee of experts in the fields of cardiovascular, renal and lipid metabolism has been assembled to aid in the training and research plan and will track professional progress to help ensure progression towards the goal of becoming an independent investigator. The project will be carried out at the University of California, San Francisco which provides an outstanding environment in which to conduct this research and develop the professional skills critical to the success of a young investigator. [
Obesity and the complications of overnutrition are increasingly important issues, as the prevalence of obesity is increasing globally. The major complication associated with obesity is the development of DM with the attendant increased risk of cardiovascular disease and heart failure. This application seeks to explore the role of lipid deposition in contributing to cardiac dysfunction and may provide important information which will help to irientifv molecular targets that mav prove amenahlfi tn thfiraheutic intervention.