Objectives
Our laboratory is focused on: (1) Elucidating the molecular mechanisms that are responsible for cardiac failure in diabetes. (2) Elucidating the molecular signals that coordinate the mitochondrial and metabolic adaptations to cardiac growth. (3) Elucidating the mechanisms by which insulin and growth factor signaling regulate cardiac mitochondrial metabolism and the adaptation of the heart to stress. (4) Elucidating the role of mitochondrial dysfunction in the pathogenesis of insulin resistance, diabetes and its complications. Our recent studies have underscored the importance of mitochondrial oxidative stress as a major mechanism leading to cardiac dysfunction in obesity and diabetes. We have shown for example that multiple abnormalities such as increased myocardial fatty acid delivery or impaired insulin signal transduction independently impair mitochondrial function and the expression of gene regulatory pathways that encode many mitochondrial proteins. We have relied heavily on transgenic and gene-targeted mice (conventional as well as conditional and cell-type restricted KO mice) to address many of these questions. We have developed a comprehensive array of approaches such as measurement of mitochondrial energetics in subcellular organelles, determination of substrate flux in intact hearts, as well as cardiovascular phenotyping in intact mice. We are also using proteomics and gene arrays to identify novel insulin-regulated targets in the mitochondria and validating these results using cell-culture models and transcriptional assays.
