Daniel Kelly's Research Focus
Dr. Kelly’s laboratory focuses on the gene transcriptional regulatory programs controlling myocyte energy metabolism and mitochondrial function during development and in disease states, with emphasis on diabetes and heart failure.
The Kelly laboratory discovered that ligand-activated nuclear receptors, including PPARs and ERRs, serve critical roles in the dynamic transcriptional control of cardiac and skeletal muscle genes involved in cellular fuel metabolism and mitochondrial function during development and in response to physiological/nutritional stress. More recently, the Kelly laboratory found that the transcriptional coactivators, PGC-1(alpha) and PGC-1β are inducible upstream regulators of cardiac nuclear receptors, placing them in a role as master regulators of mitochondrial function and biogenesis in heart and skeletal muscle.
Studies in genetically-engineered mice and in humans have shown that the PGC-1-nuclear receptor axis is dysregulated in myocardial disease states leading to mitochondrial dysfunction. An interesting feature of this dysregulation is that specific disease states (e.g., hypertension versus diabetes) cause distinct signatures of dysregulation of the PGC-1 circuit, such that disease-specific metabolomic and genomic blueprints can be defined, allowing for the development of therapeutic targets aimed at specific heart failure phenotypes.
Daniel Kelly's Research Report
Project 1: Identification of new pathways to stabilize cardiac metabolism and mitochondrial function in the failing heart
Despite recent advances in the prevention and treatment of cardiovascular disease, the prevalence of heart failure, a worldwide health threat, continues to grow. Current drug therapies for heart failure are largely directed at disturbances in the neurohormonal axis rather than targeting the myocyte. Evidence is emerging that alterations in myocyte energy metabolism and mitochondrial function contribute to the pathogenesis of heart failure. The main objective of this project is to define the molecular regulatory circuitry that controls myocardial fuel and energy metabolism in the normal and diseased heart, in order to gain insight into the early events that drive the pathologic remodeling that leads to the syndrome of heart failure and to use this information to define signatures and therapeutic targets unique to the underlying etiology (e.g., hypertension, ischemic injury, diabetes). We, and others, have found that a gene regulatory cascade, directed by the cardiac-enriched, inducible transcriptional coactivators, PPAR γ transcriptional coactivator-1α and β (PGC-1α and PGC-1β), controls the expression of genes involved in a wide array of fuel burning and mitochondrial ATP-generating processes in the cardiac myocyte. Our recent work in genetically-modified mice has shown that the PGC-1 regulatory cascade is required for postnatal metabolic maturation of the heart, including the late prenatal surge in mitochondrial biogenesis that equips the heart with the ATP-generating capacity necessary for postnatal pump function. We have also found that the activity of the PGC-1 coactivators and their nuclear receptor transcription factor targets, including peroxisome proliferator-activated receptors (PPARs) and estrogen-related receptors (ERRs), is diminished in pathologic forms of cardiac hypertrophy. These findings have led us to propose that chronic deactivation of PGC-1 signaling, as occurs in common pathophysiological conditions such as pressure overload or ischemic damage, contributes to the progressive pathologic, metabolic, and functional remodeling that leads to end-stage heart failure. Our work suggests that the metabolic basis of heart failure differs depending on the etiology (e.g. hypertension versus diabetes). We are currently utilizing loss-of-function and gain-of-function mouse and cell systems to test this hypothesis. We have assembled a multi-disciplinary team to use a systems approach, combining unbiased gene transcriptional profiling with targeted, quantitative mitochondrial proteomics, mass spectrometric-based metabolite profiling (transcriptomics, metabolomics, lipidomics), and chemical biologic screens to tease out genes and pathways relevant to the early metabolic derangements that presage heart failure. A long-term goal is to identify new targets and biomarkers for the development of metabolic modulation therapy aimed at the prevention or amelioration of common forms of heart failure.
Project 2: Unraveling the molecular links between altered skeletal muscle fuel and energy metabolism and insulin resistance
We are witnessing a virtual pandemic of obesity that is driving an alarming increase in the prevalence of type 2 diabetes. The overall objective of this project is to delineate novel gene regulatory mechanisms and downstream pathways controlling skeletal muscle fuel metabolism and mitochondrial function relevant to the consequences of chronic caloric excess. Previous studies have shown intriguing associations between derangements in muscle lipid metabolism and impaired insulin-responsive glucose uptake and utilization. However, the mechanisms involved in this proposed linkage are poorly understood. Indeed, the role of myocyte triacylglyceride accumulation as cause versus effect, or adaptive versus maladaptive, in the development of insulin resistance and glucose intolerance remains unclear. Published evidence suggests that abnormal accumulation of skeletal myocyte lipid leads to derangements within the insulin signaling pathway. However, we have shown that chronic activation of the nuclear receptor, peroxisome proliferator-activated receptor α (PPARα), as occurs in the insulin resistant state, leads to reduced muscle glucose utilization associated with myocyte lipid accumulation, independent of derangements in the insulin signaling pathway. We seek to develop a clear conceptual framework for the interaction between derangements in muscle lipid metabolism, and the development of insulin resistance and type 2 diabetes. This is being accomplished by manipulation of transcriptional regulators (PGC-1, PPAR, ERR) known to control cellular fuel metabolism and mitochondrial function in genetically-modified mice and in cells. In addition, we are using unbiased approaches including small molecule screening and ChIP-sequence-based genome-wide surveys to identify relevant molecular probes and genes/pathways, respectively. A long-term goal is to identify novel therapeutic targets relevant to obesity, insulin resistance, and diabetes.
Project 3: Toward prevention of muscle de-training
Certain conditions such as aging, chronic disease states, low gravity, and any situation that causes periods of reduced activity or immobilization leads to de-training, which is related to a reduction in muscle mitochondrial functional capacity, diminished blood vessel density, a shift away from oxidative muscle fibers, and reduced muscle mass. In such states, muscle becomes easily fatigued, reducing endurance and performance. During periods of immobilization, such as recuperation from injuries, with chronic diseases, obesity, and with aging, muscle de-training ensues. De-trained muscles result in significant reduction in performance, easy fatigability, and increased risk of musculoskeletal injury. Moreover, loss of muscle fitness predisposes to obesity, insulin resistance, and diabetes. This project seeks to establish new approaches to maintain muscle fitness and retard the de-training process. In the long-term, we seek to develop new therapeutic agents that, when combined with a modest degree of activity, will increase the time to muscle de-training during periods of reduced locomotor activity, as well as enhance muscle fitness, preventing or reducing insulin resistance and other effects of the obese state. Our laboratory has shown, using sophisticated genetically-modified mouse systems, that the PGC-1 coactivators and downstream targets control the number and function of mitochondria in skeletal muscle and heart. We seek to target the PGC-1 gene regulatory cascade to understand the mechanisms and develop new drugs that will enhance or maintain skeletal muscle mitochondrial oxidative capacity, vascularity, and the “trained” fiber type program; in effect, to maintain the beneficial effects of exercise training.
Daniel Kelly's Bio
Daniel Kelly, M.D. obtained his medical degree from the University of Illinois College of Medicine in Chicago in 1982. He was an Intern (1982-1983) and an Assistant Resident in Medicine (1983-1985) at Barnes Hospital in St. Louis. Thereafter, he did a Postdoctoral Research Fellowship in the Department of Biological Chemistry (1985-1987) followed by Clinical Cardiology Fellowship training (1987-1989) at Washington University School of Medicine. Dr. Kelly joined the Washington University School of Medicine faculty in 1989 and rapidly moved up the ranks to Professor of Medicine, Molecular Biology & Pharmacology, and Pediatrics (1999).
While at Washington University School of Medicine, Dr. Kelly held the Tobias and Hortense Lewin Professorship and served as Chief of the Cardiovascular Division (2006-2008). He was the founding Director of the Center for Cardiovascular Research at Washington University (1996).
In 2008, Dr. Kelly assumed the role of founding Scientific Director for the Sanford-Burnham Medical Research Institute at Lake Nona, Florida. The Institute serves as a site for interdisciplinary research focused on the broad area of metabolism with translational focus on diabetes, obesity, and its cardiovascular complications.
Dr. Kelly’s research interests stem from an early fascination with rare inborn errors in mitochondrial metabolism in children that 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 toward identifying therapeutic targets for phenotype-specific treatment of heart failure.
1978 B.S. (Biology) University of Illinois
1982 M.D. University of Illinois College of Medicine, Chicago, Illinois
1982-1983 Internship in Medicine, Barnes Hospital, St. Louis, Missouri
1983-1985 Assistant Resident in Medicine, Barnes Hospital, St. Louis, Missouri
1985-1987 Research Postdoctoral Fellowship, Department of Biological Chemistry, Washington University School of Medicine, St. Louis, Missouri
1987-1989 Clinical Cardiology Fellow, Washington University School of Medicine, St. Louis, Missouri
Adjunct Professor of Biomedical Sciences, University of Central Florida College of Medicine
Adjunct Professor of Medicine, University of Florida
Honors and Recognition
1997 American Society for Clinical Investigation
2001 Association of American Physicians
2008 AHA, Distinguished Achievement Award (Basic Cardiovascular Sciences Council)
2009 AHA, Basic Research Prize