A systems approach to metabolic dysregulation in the heart

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DESCRIPTION (provided by applicant): PROJECT SUMMARY / ABSTRACT This proposal details a comprehensive five-year training program for mentored career develop in academic cardiovascular medicine. The applicant has completed clinical training in cardiovascular medicine at Brigham and Women's Hospital and proposes a research program specifically constructed to provide additional essential training that will serve as the foundation for his transition towards an independent career as a physician-scientist. Through the career and scientific plans outlined, the applicant aims to leverage his prior training in cardiovascular physiology and disease with newly acquired skills in systems analysis, genomics, metabolomics and macro-molecule mass spectrometry within a structured and mentored scientific environment, in order to shed novel insight into the metabolic remodeling that underlies the pathogenesis of heart failure. A joint mentorship between Dr. Vamsi Mootha, an internationally-recognized scientist at the Broad Institute with expertise in systems analysis, genomics and metabolomics, and Dr. Ronglih Liao, an expert in cardiomyocyte biology and myocardial physiology at Brigham and Women's Hospital, has been established to foster the applicant's scientific and career development. Dr. Mootha's and Dr. Liao's laboratories will provide an ideal environment for the applicant, with state-of-the-art infrastructure, analytical skills, innumerable resources and rich scientific base required to obtain the necessary training. Additionally, both Dr. Mootha and Dr. Liao have a proven track record of mentorship, including with young investigators transitioning to faculty positions and independent laboratories. Furthermore an expert academic advisory committee of distinguished scientists and clinicians from the Harvard community will add complementary scientific expertise in a spectrum of biological specialties, while focused on the career development of the applicant. The applicant's central goal is 1) to comprehensively characterize the fundamental metabolic derangements that contribute to the pathogenesis of heart failure as well as 2) to identify the molecular regulators of this deleterious process. Towards this, the applicant proposed to utilize an innovative HPLC-mass spectrometry based platform for global metabolic assessment of myocardium and as well as organ-level flux analysis in a mouse model of post-myocardial infarct heart failure. Also, using genomic tools and systems analysis, the applicant has recently identified the transcriptional repressor TGIF1 as a putative regulator of cardiac metabolism, and will determine the role of TGIF1 in mediating metabolic gene expression, metabolic function and cell contractility in isolated adult cardiomyocytes, in-vitro. These two complementary, yet independent, Aims serve to integrate both large scale discovery science with single gene hypothesis-driven investigation. Collectively, the experience gained from the proposed experiments and structural career development plan will serve as the foundation for the applicant's independent academic career as a physician-scientist. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Despite advances in the diagnosis and treatment of cardiovascular disease, the number of patients with heart failure continues to rise at epidemic rates. This proposal aims to identify the changes that occur in heart metabolism during the course of heart failure and the mechanisms that underlie these deleterious changes. In doing so, we hope to identify new approaches to treat heart failure and cardiovascular disease.