Mechanistic insights into the role of Zfp36 in cardiac lipid metabolism and cardiac response to pressure overload

The major goal of this proposal is to elucidate the role of TTP in FA catabolism, characterize the underlying mechanism for this regulation, and investigate the role of this regulation in the development of HF. This proposal is novel in numerous ways as it will 1) study, for the first time, the role of an RNA-binding protein in mammalian cardiac FA metabolism, 2) elucidate a novel regulatory pathway in FA metabolism through TTP, 3) investigate whether TTP directly targets a key enzyme, PPARα, in FA metabolism, 4) study the role of TTP in the development of HF by regulating FA metabolism, and 6) use novel and interesting mouse models. More specifically, I will use csTTP-KO mice to directly examine the role of TTP in cardiac lipid metabolism. I have and will also use TNFα receptor (TNFR)-1 and -2 KO (TNFR1/2-/-), and TNFR1/2-/-/TTP-/- mice, which lack the systemic inflammation observed in TTP-/- mice (4), and were designed to characterize the biological functions of TTP, independent of inflammation. My proposal will put TTP on the map of metabolism as a key regulator of FA utilization in the heart. Above and beyond the scientific and experimental novelty, the proposed studies may provide the foundation for a novel therapeutic approach for HF.