Dr. Kelly's research interests stem from an early fascination with rare inborn errors in mitochondrial metabolism in children which cause sudden death and heart failure. As a young researcher at Washington University, Dr. Kelly defined the genetic basis for a common inborn error in mitochondrial fatty acid oxidation, work that led to the development of practical screening tests for newborns. Thereafter, he became interested in how similar derangements in cardiac energy metabolism contribute to heart failure and sudden death in common acquired forms of mitochondrial diseases caused by hypertension, ischemic injury, and diabetes. His work defined the transcriptional regulatory axis involved in the control of cardiac fuel and energy metabolism through pioneering fundamental work on nuclear receptors including the PPARs, estrogen-related receptors (ERRs), and their transcriptional coactivator PGC-1. The Kelly laboratory has identified molecular "switches" in this regulatory pathway that potentially define distinct forms of heart failure, an important step towards identifying therapeutic targets for phenotype-specific treatment of heart failure. More recently, the Kelly laboratory has applied proteomic and metabolomic approaches to investigating the metabolic origins of heart failure.