The role and regulation of the LKB1-AMPK axis in diabetic cardiomyopathy

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DESCRIPTION (provided by applicant): This proposal details the research and training plan for a 5-year mentored award designed to facilitate the principal investigator's career development as a newly appointed junior faculty member physician-scientist at the Boston University School of Medicine. This award will expand the investigator's previous research using new models and methods. The immediate career goal of the investigator is to explore energetic signaling via AMPK-LKB1, cardiac metabolism, and cardiomyocyte biology in diabetic heart failure. The principal investigator's educational background includes clinical cardiology training, a post-doctoral research fellowship in cardiology, and Ph.D. at the Yale University School of Medicine. Dr. Wilson Colucci, an expert in cardiomyocyte biology and heart failure, will mentor the principal investigator in the section of Cardiovascular Medicine at Boston University School of Medicine where he is Professor of Medicine, Chief of Cardiovascular Medicine, and the Director of the Myocardial Biology Unit. The mentor and the institution have strong tract records of scientific accomplishment and successful career development of junior faculty, with established multi-disciplinary programs in cardiomyocyte biology, cellular signaling, proteomics, diabetes, and heart failure. The training plan outlined in this award includes didactic lectures, one-on-one and group mentoring, and attendance at national/international meetings in cardio-metabolic research. The principal investigator aspires to utilize the acquired training, expertise, and scientific data to apply for independent research funding at the conclusion of this award. The overall goal of this proposal is to understand the role of AMPK in the heart as a coordinator of energetic signaling in murine models of type 2 diabetes and to explore regulation and pharmacologic activation of AMPK via the upstream AMPK kinase (AMPKK), LKB1. The first aim of this proposal is to investigate whether intrinsic AMPK activation is deranged in the development and progression of diabetic heart failure. A key outcome will be to investigate whether intrinsic AMPK activation is decreased in the diabetic heart and whether AMPK deficiency exacerbates diabetic heart disease. The second aim is to examine the impact of LKB1 post- translational modifications on LKB1-AMPK signaling in the diabetic heart, and test the contribution of LKB1 to AMPK activation in the diabetic heart using hearts deficient in LKB1. The third aim is to assess whether extrinsic AMPK activation is improves the functional and metabolic phenotype of the diabetic heart, particularly in response to acute changes in workload, evaluating changes in reactive oxygen species generation and mitochondrial function. In summary, this proposal investigates an important signaling pathway in the diabetic heart while allowing the investigator to acrue the training and expertise to successfully become an independent physician-scientist.