The goal of this proposal is to extend my training as an independent scientist in the field of molecular hepatology and discover mechanisms of nuclear receptor regulation of hepatic metabolism. To this end, I have selected the Molecular and Cellular Biology Department at Baylor College of Medicine to continue my transition to become an independent investigator at an academic institution. This proposal outlines an extensive Research Strategy that is complemented by several areas of training, which includes several courses directly related to my studies in Specific Aim 1, meeting with my junior faculty research committee, and attendance and participation of multiple seminars throughout the Texas Medical Center. My Research Strategy will determine whole genomic-changes in nuclear receptor binding in a Wilson's disease animal model (Atp7b-/- mouse). Wilson's disease is an autosomal recessive disorder caused by loss of function mutations in the Cu- transporting P-type ATPase, ATP7b, which results in a variety of symptoms, including hepatic copper accumulation, cholestasis, cirrhosis, liver failure, and neurological dysfunction. Treatments for Wilson's disease are limited to chelation therapy, zinc therapy, or liver transplantation. Chelation therapy has been associated with several side-effects and poor patient compliance, and uncontrolled Wilson's disease can result in liver failure and requires liver transplantation for patient survival. Despite the severity of Wilson's disease, insights regarding copper-mediated changes in metabolism are limited. My post-doctoral studies established a defect in nuclear receptor activity in the Atp7b-/- mouse and Wilson's disease patients. The proposed K01 experiments continue those studies to determine the broader changes in nuclear receptor promoter occupancy and target gene mRNA expression, as well as test if targeting the nuclear receptors decreases the liver pathology observed in the Atp7b-/- mouse.
Wilson's disease is characterized by excessive hepatic copper and results in liver failure if not treated or diagnosed at an advanced stage. This proposal will determine novel nuclear receptor signaling pathways that may serve as useful therapeutic targets for the future treatment of Wilson's disease.