Research Description

My research examines the metabolic basis of impaired contractile function in the diseased heart. At the most fundamental level the research effort elucidates intracellular mechanisms of metabolic flux regulation. A particular focus is on heart failure and the maladaptive metabolic changes that occur in response to pathological (chronic pressure overload and hypertension, post MI remodeling) or metabolic stresses (diabetes, nutrient overload) on the heart. Active research protocols assess genomic, transcriptional and postranslational regulation of metabolic flux in the heart during health and disease using a combination of schemes to manipulate gene activation and suppression in the in vivo heart. By elucidating fundamental mechanisms that lead to dysregulated metabolic activity in the diseased heart, the research group is then able to identify potential therapeutic targets and devise therapeutic regimens to improve cardiac function and mitigate the progression decompensatory process of cardiac hypertrophy toward overt heart failure. Prospective therapies that tested include pharmacologic approaches, gene therapy protocols, and dietary regimens. Using these approaches we have been able to counter metabolic inefficiencies in energy metabolism and metabolic signaling within cardiomyocytes of the pathological heart. A particularly exciting area of investigation has been the dynamics of lipid metabolism in the heart, exploring shifts in the reciprocal mechanisms of lipid storage and oxidation that influence underlying mechanisms of lipolytic signaling for metabolic gene activation through ligand binding nuclear receptors and the formation of physiologically active or lipotoxic lipid intermediates. Most recently the laboratories have been examining the crosstalk between the heart peripheral organs, in health and disease, that influence systemic metabolism and insulin sensitivity. A hallmark of my research program has been the use of stable isotope kinetics to assess enzyme activity, quantify metabolic flux, intracellular transport rates, and metabolite turnover within the intact beating heart using a combination of NMR spectroscopy of the heart and end-point, quantitative analytics with LC/MS, in vitro NMR, and proteomic analysis.