A Functional Role for Prolyl Hydroxylases (PHDs) in Cardiomyopathy

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DESCRIPTION (provided by applicant): This proposal describes a 4 year training program for career development in academic cardiovascular (CV) medicine. The principal investigator has completed clinical and research training in CV medicine at Brigham and Women's Hospital and will embark on a research program designed to provide additional scientific training required for an independent biomedical research career. This program will provide sound principles and expertise for studying the master transcription factor Hypoxia-Inducible Factor-a (HIFa) as it applies to myocyte biology and heart failure. A joint mentorship between Dr. William Kaelin, a Howard Hughes Investigator, Professor of Medicine at Harvard Medical School and a pioneer in cellular signaling in hypoxia, and Dr. Ronglin Liao, associate professor of medicine at Harvard Medical School and an expert in cardiomyocyte biology, has been forged to foster the applicant's scientific and career development. The investigator has established a novel model for spontaneous heart failure in mice deficient in PHD2, a prolyl hydroxylase that regulates the stabilization and activity of HIFa. The specific aims of this proposal are: 1) To determine the functional consequence of PHD2 inactivation in the cardiomycoyte in vivo and ex vivo. 2) To test whether PHD3 partially compensates for PHD2 loss in vivo and specifically in the heart 3) To test the hypothesis that HIFa is necessary and sufficient for the development of cardiomyopathy seen in cardiac- specific PHD2-/- mice. RELEVANCE (See instructions): Heart failure represents an enormous medical and societal burden, affecting over 5 million people in the USA, and its incidence is only increasing with an aging population and prolongation of the lives of cardiac patients. This research aims to understand the fundamental mechanisms of heart failure with the ultimate goal of finding new therapies to prevent and treat this devastating illness. (End of Abstract)