KELLY LAB RESEARCH INTERESTS
Project 1: Unraveling the molecular links between altered myocardial metabolism and heart failure
Heart failure and its attendant morbidity and mortality is a significant and growing problem in the US . Little is known about the fundamental events that dictate the progression from the stable hypertrophied heart to decompensated ventricular dysfunction leading to the syndrome of heart failure. Evidence is emerging that derangements in cardiac fuel utilization and bioenergetics contribute to the pathologic remodeling of the hypertrophied heart. Nuclear receptor transcription factors control the expression of genes involved in myocardial energy metabolism. Recent evidence, generated by our group and others, indicates that nuclear receptors such as peroxisome proliferator-activated receptors (PPARs) and estrogen-related receptors (ERRs) and their coactivator, PGC-1α, become deactivated in the pathologically hypertrophied heart. Conversely, the activity of these pathways are maintained in physiologic forms of adaptive hypertrophy. We hypothesize that in the pathologically hypertrophied heart, deactivation of certain components of the gene regulatory cascade downstream of the inducible coactivator PGC-1α, leads to altered energetics and progressive ventricular dysfunction. We are currently using gain-of-function and loss-of-function strategies in mice and cultured cardiac myocytes to build upon our recent progress in delineating the regulatory pathways upstream and downstream of the PGC-1α gene regulatory cascade, to define the biologic function of this pathway, and to determine whether deactivation of specific components within this transcriptional regulatory circuitry contribute to the pathologic process that leads to irreversible ventricular dysfunction and heart failure in the context of chronic pressure overload. A long-term goal is to identify new targets for the development of metabolic modulation therapy aimed at the prevention or amelioration of common forms of heart failure.
Project 2: Skeletal Muscle Nuclear Receptor Signaling
We are witnessing an emerging epidemic of obesity and type 2 diabetes. The peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that control the expression of genes involved in cellular fatty acid metabolism. Using genetically-modified mice, we have recently unveiled exciting links between the muscle PPARα pathway and obesity-related insulin resistance. PPARα deficiency protects against insulin resistance and diabetes despite the development of an obese phenotype. Conversely, transgenic mice with muscle-specific overexpression of PPARα develop diet-induced glucose intolerance and insulin resistance despite maintaining a lean phenotype. This project is designed to test the hypothesis that in states of caloric excess, re-direction of lipid to extra-adipose tissues, such as skeletal muscle, triggers PPARα-driven increases in mitochondrial fatty acid oxidation and reciprocal reduction in glucose utilization through gene regulatory mechanisms independent of the insulin signaling machinery. It is also proposed that over the long-term, increased fatty acid flux through oxidative pathways leads to muscle mitochondrial dysfunction. The objectives of this proposal will be achieved using genetically-modified mice and UCP-DTA mice, a murine model of Metabolic Syndrome and type 2 diabetes. We also seek to explore the potential role of the related nuclear receptor PPARbeta/delta in controlling skeletal muscle metabolism and function (exercise). The role of nuclear receptor coactivators, PGC-1α and PGC-1beta , on muscle metabolism, and insulin resistance is also being studied with emphasis on mitochondrial biogenesis. In the short-term we seek to develop a clear conceptual framework for the interaction between derangements in muscle lipid metabolism, and the development of diabetes. A long-term goal is to identify novel therapeutic targets relevant to Metabolic Syndrome.
Project 3: Towards Understanding the Pathogenesis of Diabetic Cardiac Dysfunction
Cardiac dysfunction is a common and important manifestation of diabetes mellitus. It is well recognized that cardiomyopathy occurs frequently in diabetic patients in the absence of known cardiac risk factors. Although little is known about the pathogenesis of diabetic cardiomyopathy, evidence is emerging that cardiac dysfunction in the diabetic heart is related to perturbations in myocardial metabolism caused primarily or secondarily by insulin deficiency or resistance. In uncontrolled diabetes, the myocardial extraction and utilization of fat is markedly increased such that the diabetic heart relies almost exclusively on mitochondrial fatty acid oxidation (FAO) for its ATP requirements. Recent studies have defined an important role for the lipid-activated transcription factor, the peroxisome proliferator-activated receptorα (PPARα), in the control of cardiac fatty acid utilization pathways. Our preliminary data indicates that the activation of cardiac fatty acid utilization in the diabetic heart is mediated by the PPARα gene regulatory pathway. This project is designed to test the hypothesis that lipid metabolic alterations secondary to increased activity of PPARα lead to pathologic remodeling in the diabetic heart. Such pathologic remodeling could occur due to increased oxygen consumption or through toxic lipid intermediates generated by peroxisomal or mitochondrial pathways. Our preliminary results also suggest that the related nuclear receptor, PPARbeta/delta promotes beneficial metabolic effects in the diabetic heart. These hypotheses are being tested by phenotypic characterization of mice with cardiac-specific overexpression of PPARα or PPARbeta/delta. In a separate series of studies, we are using genetically-modified mice to investigate the effects of myocyte glucose overload on the development of diabetic cardiomyopathy. The long term goal of this project is to delineate the precise molecular and metabolic bases for diabetic cardiomyopathy including identification of specific lipid mediators of cardiac dysfunction that could serve as biomarkers or therapeutic targets. This work should lead to the development of novel therapeutic strategies aimed at modulating cardiac lipid metabolism to reduce the cardiovascular morbidity and mortality in diabetic patients.