Regulation of Lipotoxicity by the non-coding RNA gadd7

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DESCRIPTION (provided by applicant): Lipotoxicity is the process by which non-adipose tissues, such as the heart and pancreas, accumulate an excess of fatty acids leading to cellular dysfunction and cell death. Lipotoxic-cell death is implicated in the development of human metabolic diseases such as cardiomyopathy and type 2 diabetes. The generation of reactive oxygen species (ROS) and activation of the ER stress response are central to lipotoxic-cell death. However, the exact molecular pathways involved in this process have not been well characterized. To elucidate the key players in the lipotoxic-response, a genetic screen in Chinese hamster ovary cells was carried out by our lab. The screen led to the identification of the non-coding RNA gadd7, which has no known function. Gadd7 expression is induced by the ROS precussor H2O2 and several of its gene family members are associated with the ER stress response. These results and the isolation of gadd7 in our screen suggest a role for gadd7 in the lipotoxic-response. This proposal will test the hypothesis that gadd7 is regulated by lipotoxic-conditions and functions to regulate a program of gene expression in the lipotoxic- response. My aims are to: 1. Confirm the role of gadd7 in lipotoxicity, 2. Characterize the step in the lipotoxic-response where gadd7 disruption inhibits lipotoxic-cell death, 3. Determine the function of gadd7 in the lipotoxic-response by assessing if gadd7 functions as a regulatory RNA. The excess accumulation of fat is implicated in the pathogenesis of diseases like heart failure and type 2 diabetes. The proposed research will increase our understanding of how excess fat disrupts organ function, contributing to the onset of these diseases, and may provide new avenues of treatment and therapy.