Jean E Schaffer MD
While fatty acids are critical for many cellular functions, accumulation of excess fatty acids in non-adipose tissues leads to cell dysfunction and cell death. This lipotoxicity plays an important role in the pathogenesis of heart failure and other complications of diabetes. The goals of our work are to characterize the fundamental cellular mechanisms of metabolic stress from substrate excess, and to understand how this process contributes to diabetes complications. Through our basic studies involving genetic screens in cultured cells, we have identified critical molecular players in the lipotoxic response. Unexpectedly, this work uncovered a role for non-canonical small nucleolar RNAs in the response to metabolic and oxidative stress. Ongoing studies are focused on the molecular mechanisms through which these regulatory RNAs act. We are also extending our findings to mouse models of diabetes complications to elucidate the pathophysiological roles of genes identified in our screens. In an effort to translate our basic studies to an understanding of human disease, we are collaborating with clinical investigators to define the relationship between altered systemic lipid metabolism and early diabetic cardiomyopathy in asymptomatic human subjects with type 2 diabetes. Our long-term goal is to develop novel lipid biomarkers and non-invasive methods for diagnosing the earliest structural and functional abnormalities in diabetic cardiomyopathy and for guiding therapy.