Although excess lipid accumulation in non-adipose tissues is initially well tolerated, this metabolic excess ultimately causes cell dysfunction and cell death that is linked to the pathogenesis of complications of diabetes and obesity. Using a genetic screen, we discovered that RNASET2, a T2 endoribonuclease, is a critical mediator of oxidative stress damage and cell death in response to lipotoxicity. This study will elucidate the mechanism of action of RNASET2, by identifying the RNAs that this enzyme degrades, by elucidating the pathways through which RNA substrates are delivered to RNASET2, and by examining the contributions of RNASET2 to the pathogenesis of cardiac lipotoxicity in a mouse model. The results of these studies will provide new insights into the lipotoxic response to excess lipid accumulation in cardiovascular complications of metabolic diseases.
Diabetes is associated with serious complications that arise from deposition of excess fats in tissues such as the heart. The studies proposed in this application will characterize how excess fat leads to dysfunction and death of cells. We will extend our findings to models of diabetic heart disease to understand how this process affects heart muscle function. Given the prevalence, morbidity, and mortality of heart failure in patients with diabetes, further understanding of this disease process will facilitate the development of new treatments and preventative strategies.
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