CHAMP RNA HELICASE · Function, Mechanism, and Regulation of Mammalian Mov10L1 RNA Helicase

Adult cardiac myocytes retain the ability to respond to a variety of stimuli by hypertrophic growth. Hypertrophy is initially beneficial, permitting enhanced cardiac output; it can ultimately become deleterious and result in cardiomyopathy, heart failure, and sudden death. Mitogenic signaling drives cell cycle progression as consequences of their effects on cyclins, which interact with cyclin-dependent kinases and cyclin-dependent kinase inhibitors. Recent work showed that CHAMP has antihypertrophic activity, which requires the conserved ATPase motif that is characteristic of RNA helicase superfamilies 1 and 2, and is associated with up-regulation of the cell cycle inhibitor p21CIP1 and p27KIP1. CHAMP is localized in the cytoplasm of cardiomyocytes and is likely regulates its target RNA at the level of translation and degradation. The regulation p21CIP1 and p27KIP1 translation levels controls the proliferation of cardiomyocytes by inhibiting cell cycle progression. However, very little is known regarding the molecular mechanism of how RNA helicases regulate translation. To date detailed enzymology regarding the mechanical transduction of RNA helicases is scarcely known, especially from superfamily 1 to which CHAMP is identified with. This proposal is aim to decipher the molecular mechanism of a putative RNA helicase CHAMP and how it regulates mRNA metabolism of genes essential for the heart development during prenatal stages and regulates CDKI’s mRNA in postnatal stages. The research program will integrate state of the art molecular biochemistry and biophysics approach with medicinal translational research. An interdisciplinary structured based team will be assembled to integrate knowledge, and capacity from molecular to physiological aspects of cardio myocytes hypertrophy. This will result from integration of key enzymatic regulators as CHAMP to the physiological regulation of cardiomyocytes hypertrophy response in human at the molecular level of mRNA metabolism.