(from the application): The enzyme 5'AMPK is increasingly regarded as a master controller of cellular metabolism. In the senescent heart, there appear to be changes in this enzyme system, either in the upstream regulation of 5'AMPK, the amount of the enzyme, or the downstream responses to activation of the enzyme. The overall goal of the proposed research is to define on a molecular level how this enzyme is regulated in the heart, how that regulation changes with age, and what role changes in this enzyme with age play in causing the insulin resistance that occurs with aging. The initial step in accomplishing this goal is to determine how the amount of mRNA and protein of this enzyme change with age, and define more completely what regulates 5'AMPK activity. The second step is to determine whether changes in the 5'AMPK system with age contribute to insulin resistance, and whether age-associated insulin resistance can be reversed with chronic pharmacological stimulation of 5'AMPK. This second step will be accomplished using a unique preparation where the following key steps in the 5'AMPK pathway can be measured in isolated hearts: left ventricular contractile function, the concentrations of known and putative allosteric regulators of 5'AMPK, and cardiac uptake of oxygen, glucose, lactate and free fatty acids. The applicant's long-term career goal is to become an independent investigator studying age-associated changes in myocardial metabolism, and their role in heart disease. In the applicant's recent studies it has become apparent that accomplishing this goal will require learning cellular and molecular techniques that can be applied to studying myocardial metabolism during senescence. The techniques in the proposed research are designed to complement the applicant's experience in cardiac energetics/NMR spectroscopy. Through interactions with Dr. Lakatta and the strong biogerontology research community at Boston University School of Medicine (two training grants and a Gerontology Center), the applicant will be instructed in the methodological issues central to the study of biogerontology research.
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