Obesity and diabetes are complex metabolic problems of pandemic proportion in industrialized nations, contributing to significant cardiovascular morbidity and mortality. In patients with diabetes, heart failure occurs commonly, often in the absence of coronary risk factors. There is now clear evidence that myocardial metabolic abnormalities are linked to the development of cardiomyopathy. Recent studies from the sponsor's lab have shown that the fatty acid-induced transcription factor, peroxisome proliferator-activated receptor alpha (PPARoc) is activated in the diabetic heart. My preliminary data demonstrate that activation of cardiac PPARa presages the onset of overt diabetes. This activation of PPARa-is necessary for mitochondrial biogenesis mediated by the transcriptional coactivator, PPAR-y coactivator-1 alpha (PGC-1a). The current proposal is designed to test the hypothesis that this PPARadependent, PGC-1a mediated mitochondrial biogenesis is initially an adaptive response of the heart to cope with high rates of fatty acid delivery. However, we propose that later in the stages of overt diabetes, dysregulation of PGC-1a leads to mitochondrial dysfunction and cardiac dysfunction. The hypotheses will be tested using genetically engineered PGC-1a gain-of-function and loss-of-function mouse models and cell culture promoter-reporter studies to delineate the mechanisms by which PPARa regulates PGC-1a. Experiments in Specific Aim 1 are designed to define the regulatory mechanisms by which PPARa induces PGC-1a gene expression. The goal of Specific Aim 2 is to test the hypothesis that PGC-1a is required to maintain normal mitochondrial number and function in the diabetic heart.
Specific Aim 3 is designed to assess potential """"""""rescue"""""""" strategies to prevent the decline in PGC-1a associated with overt diabetes, and thus maintain normal mitochondrial and cardiac function. A long-term goal is to develop therapeutic strategies targeted at the maladaptive metabolic pathways downstream of PPARa in order to preserve cardiac function in the diabetic heart. The candidate is a pediatric intensivist with an interest in perturbations in cardiac energy metabolism during critical illness. She has a keen interest in becoming a physician-scientist and seeks a formal, mentored training program to help her develop the skills necessary to become an independent investigator. The proposed research in the lab of Dr. Daniel Kelly will provide important training and mentorship crucial for her development into a successful clinician-scientist.
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