Daniel P. Kelly, M.D.

DEPARTMENT OF Internal Medicine
Keywords: diabetes, gene expression, lipids, metabolism, transcription

Our research focuses on gene regulatory mechanisms and cellular 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. Ligand-activated nuclear receptor transcription factors such as estrogen-related receptor alpha (ERRalpha) or peroxisome proliferator-activated receptors (PPARs) and their coactivator, PGC-1, serve pivotal roles in the developmental and physiologic control of mitochondrial function in heart and skeletal muscle. PPARalpha-null and ERRalpha-null mice exhibit stress-induced phenotypes that serve as models for the metabolic/functional derangements known to occur in heart failure. PGC-1alpha null mice exhibit multi-system energy metabolic derangements that become manifest in response to physiologic stress. We are currently generating and characterizing mice with conditional “knockouts” and overexpression of the other members of the PPAR and PGC-1 families to assess relevant biologic roles. Mechanistic studies in cells complement the in vivo studies to define gene targets and biologic functions of the PGC-1 regulatory cascade. In the long-term, we seek to assess the adaptive versus maladaptive roles of these factors in common diseases such as diabetes and heart failure. Nuclear receptors, as ligand-activated are an attractive target for the development of novel therapeutic strategies.