Keith Cox has shown an early and committed interest in developing mouse models to study myocardial disease. His PhD. training involved the generation and manipulation of transgenic and gene targeted mouse models. We propose to investigate the interplay between energy metabolism and the regulation of myocardial homeostasis and gene expression by using mouse models of metabolic cardiomyopathy. Long- chain fatty acid beta-oxidation, the predominant source of ATP in the working heart will be disrupted at precise points along the metabolic pathway by ablating the activity of specific catalytic enzymes essential for mitochondrial beta-oxidation using genetic or pharmacological methods. Long-chain fatty acid oxidation (FAO) will be disrupted at two levels: (1) at long-chain fatty acid transesterification to carnitine prior to translocation into the mitochondrial matrix and (2) the beta-oxidation rate-regulating step catalyzed by long-chain acyl-coenzyme A dehydrogenases (Acadl) and very long-chain acyl-coenzyme A dehydrogenases (Acadvl). Mice with null mutations in Acadl and Acadvl have been generated. Disrupting FAO at these points in the metabolic pathway will allow myocardial structure/function, gene expression, and cell signaling events to be investigated with or without elevations of intracellular long-chain acylcarnitines, considered to be toxic and arrhythmogenic. By targeting these levels, the pathogenesis of cardiomyopathy associated with disrupted beta-oxidation can be studied together or apart from the influence of abnormal, toxic metabolites. The Division of Molecular Cardiovascular Biology at Children's Medical Center of the University of Cincinnati is internationally known for its work in the development and use of mouse models to advance understanding of cardiovascular disease. The co-sponsors, Jeffery Molkentin and Jeffrey Robbins have actively and successfully led research programs using mouse models to study the development and progression of cardiac hypertrophy is disease.
