Daniel P. Kelly, M.D.

RESEARCH INTEREST

Our research focuses on gene transcriptional regulatory mechanisms and signaling events involved in the control of mitochondrial function. Evidence is emerging that perturbations in mitochondrial energy metabolism play a role in the development of inborn and acquired forms of cardiovascular disease and diabetes mellitus. Previously, we found that the ligand-activated transcription factor, PPARa and its coactivator, PGC-1 play a pivotal role in the developmental and physiologic control of mitochondrial function and number in heart. PPARa-null mice exhibit a stress-induced phenotype that serves as a model for genetic and acquired forms of hypertrophic cardiomyopathy in which cardiac lipid and energy balance is deranged. In contrast, mice with cardiac-specific overexpression of PPARa exhibit a phenotype similar to the diabetic heart. The transcriptional coactivator, PGC-1, is a regulator of mitochondrial biogenesis during cardiac development. Conditional PGC-1 gain-of-function and loss-of-function studies are currently being performed with cardiac myocytes in culture and in genetically engineered mice to further characterize the role of PGC-1 in mitochondrial biogenesis and energy production programs. Gene expression array studies combined with candidate gene analyses are also being performed to identify new PGC-1 interacting proteins and to identify candidate genetic modifiers of the cardiac disease phenotype in humans. The long-term goal of our studies is to define the role of derangements in mitochondrial function in the pathogenesis of heart failure, diabetes mellitus, and obesity. Lastly, PPAR/PGC-1 as a ligand-activated complex, is a target for the development of novel therapeutic strategies.

SELECTED PUBLICATIONS