Daniel P. Kelly, MD
Lewin Professor and Chief, Cardiovascular Division
Director, Center for Cardiovascular Research

Office location: 810 Clinical Sciences Research Bldg., North Tower Addition
Admin. Office Telephone: 314/747-3032
Research Office Telephone: 314/362-8908
Fax: 314/454-5550
E-mail: dkelly@im.wustl.edu

Current Research Interests

The Kelly laboratory is interested in regulatory mechanisms related to the control of cardiac energy metabolism in the developing and diseased heart.  We have found that a member of the nuclear hormone receptor superfamily, the peroxisome proliferator-activated receptor a (PPARa), serves as a key regulator of mitochondrial energy production in the normal postnatal mammalian heart.  The activity of PPARa is reduced in the hypertrophied and failing heart.  Conversely, PPARa activity is abnormally “super-activated” in the diabetic heart.  To model these disease states, genetically modified mice with reduced or increased cardiac PPARa function have been developed.  Using the PPARa mouse models, the pathophysiologic conditions of hypertension, myocardial infarction, and exercise stress are being re-created through physiologic manipulations.  Concurrent with these studies, cardiac metabolic imaging using positron emission tomography (PET) are being conducted in humans with various forms of myocardial diseases due to ischemia, hypertension, and diabetes.  These experimental strategies, spanning the laboratory bench to the bedside, will guide the development of new approaches to risk stratify and treat patients at risk for heart failure based on patterns of altered cardiac metabolism.  The long-term goal of these studies is to determine whether new therapeutic approaches aimed at the PPARa complex show promise to prevent heart failure and sudden death in common diseases such as hypertension and diabetes mellitus.  Training opportunities for pre and post-doctoral trainees with both M.D. and Ph.D. backgrounds are available within each of the current projects

Recent publications

Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP: Fatty acid oxidation enzyme gene expression is downregulated in the failing heart.  Circulation 1996;94:2837-2842.

Barger PM, Brandt J, Leone TC, Weinheimer CJ, and Kelly DP:  Deactivation of the peroxisome proliferator-activated receptor a during cardiac hypertrophic growth. J. Clin. Invest. 2000;105:1723-1730.

Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros D, and Kelly DP:  PPARg coactivator-1 (PGC-1) promotes cardiac mitochondrial biogenesis.  J. Clin. Invest. 2000;106:847-856.

Huss JM, Levy FH and Kelly DP:  Hypoxia inhibits the PPARa/RXR gene regulatory pathway in cardiac myocytes. A mechanism for O₂-dependent modulation of mitochondrial fatty acid oxidation.  J. Biol. Chem. 2001;276:27605-27612.

Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk G, and Kelly DP: The cardiac phenotype induced by PPARa overexpression mimics that caused by diabetes mellitus.  J. Clin. Invest. 2002;109:121-13

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