O-GlcNAcylation and YAP: Defining a novel pathway in heart failure

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Project Summary/Abstract: Every year, approximately 550,000 Americans are diagnosed with heart failure. Half of these patients die within 5 years of diagnosis. Several lines of evidence suggest that a post translational modification of proteins, O-GlcNAcylation (OGN), plays a key role in the response of the heart to stress, regulating both health and disease. I discovered chronic exposure to increased OGN causes heart failure, whereas decreased OGN can protect the heart. However, we lack detailed understanding of how OGN contributes to heart health and disease. This gap in knowledge hinders the development of O-GlcNAc-targeted therapies to prevent heart failure. OGN occurs on thousands of proteins in the heart and is regulated by only two enzymes, OGT (adds modification) and OGA (removes modification). Myocardial OGN is increased in failing hearts, but it was unknown if increased OGN was a cause of heart failure. To answer this question, I developed a novel line of transgenic mice overexpressing either OGT, or OGA, in myocardium. OGT hearts have more OGN and these mice have myocardial hypertrophy, heart failure and die prematurely from arrhythmias. In contrast, OGA animals had less OGN and were protected against cardiac stress. My new findings support a role for the Yes Associated Protein (YAP) in causing myocardial hypertrophy in response to excess OGN. The short-term goal of this proposal is to execute complementary research and career development plans to address these gaps in knowledge and position myself as a cardiac O-GlcNAc expert. The long-term goal of this proposal is to use the knowledge gained to facilitate the development of O-GlcNAc targeted therapies for heart failure. Here, I propose to test the specific hypothesis that excess OGN activates YAP and modulates adverse cardiac remodeling through enhanced transcription of pro- hypertrophic genes. The 5-year career development plan proposed here will provide me formal training in four crucial areas: (1) Advanced techniques in glycobiology; (2) advanced training in protein mass spectrometry; (3) proficiency in protein bioinformatics; (4) enhanced grant writing and leadership skills. At the conclusion of this award period, I will have acquired the skills and training necessary to become a leader in the area of cardiac O-GlcNAc biology, an under-explored area of scientific investigation that shows great promise for translation into novel therapies.