I received my PhD from the University of California, Davis in Biochemistry. I then pursued postdoctoral training in the laboratory of Michel Lazdunski (University of Nice, FRANCE) followed by a fellowship with Solomon Snyder (Johns Hopkins Medical School). I then joined the Faculty at the University of Maryland Medical School. I was promoted to Professor in 1991. I was appointed Director of the School of Medicine MD/PhD Program in 1996.
Research Interests:We study the fundamental properties of heart cells and the impact of intracellular signaling mechanisms on the regulation of cardiac myocyte function. Calcium is a central signaling ion in heart muscle and over the years many investigations have helped to define the molecular elements underlying calcium signaling in cardiac cells. During excitation-contraction (EC) coupling in cardiac myocytes the influx of Ca2+ ions carried by the Ca2+ current (ICa) activates a large release of Ca2+ from intracellular stores in the sarcoplasmic reticulum (SR) via the SR Ca2+ release channel. The subsequent declining phase of this [Ca2+]i transient is due, in part, to Ca2+ reuptake mediated by the SR Ca2+ pump. Thus this movement of Ca2+ ions is a central feature of heart cell function. Over the years our laboratory has focused on intracellular signaling pathways that contribute to the precise physiological control of Ca2+ signaling in heart.
Angiotensin II signaling in Heart Cells -- In one series of projects we have defined how the hormone, angiotensin II, increases contractility by regulating Ca2+ currents, various protein kinases and phospholipases in intact cardiac cells. These studies have defined intracellular signaling cascades in cardiac myocytes that are activated by several distinct hormone receptors located on the cell surface. These studies not only reveal how this hormone regulates heart cell contractility but also provide insight into mechanisms that may underlie pathological processes such as heart failure or cardiomyopathy.
Role of Protein Phosphatases in Cardiac Cell Function -- Through experiments in which we directly injected proteins into intact heat cells, we have recently discovered a crucial role of phosphatase enzymes in controlling EC coupling. Thus it is clear that protein dephosphorylation reactions are important regulatory mechanisms in heart. These results have led to studies in which we are examining the localization and expression of several protein phosphatase enzymes in cardiac cells. These studies may have important implications in the pathology associated with failing heart.
Potassium Channel Regulation in heart cells -- Outward rectifying potassium channels play a crucial role in repolarizing the heart cell leading to relaxation during each beat. Recently we have found a novel regulatory mechanism that inhibits several K channels and leads to enhanced contractility as a result. This mechanism is mediated by a cellular protein known as FKBP12. Ongoing research is focused on studying the mechanism of K channel regulation in heart.
Stem Cell Therapy in Heart Disease -- Since massive irreversible loss of cardiac myocytes occurs following myocardial injury, injection of bone marrow-derived human mesenchymal stem cells (hMSCs) has emerged as a promising therapeutic intervention. Despite the growing enthusiasm for this stem cell therapy, the understanding of how hMSCs evoke cardiac improvement is ever more controversial. We currently focus on hypothesis hMSCs provide specific benefit directly to damaged ventricular myocytes. Through a range of high resolution imaging physiological and molecular techniques we have examined the interactions of hMSCs and cardiac myocytes in culture when system is subjected to a variety of stress stimuli. We have found that hMSCs prevent damage, seen as chaotic calcium signaling behavior in cardiac cells, evoked by bacterial endotoxin or inflammatory cytokine agents. These effects are linked to a genetic reprogramming of cardiac myocytes during stress events. These results reveal new evidence that hMSCs elicit protective and reparative effects on cardiac tissue through molecular reprogramming of the cardiac myocytes themselves. Thus these studies provide novel new insight into the cellular and molecular mechanisms that underlie the therapeutic benefit of hMSCs in the setting of heart failure.
Research Images:Ca Signaling in Heart Cells
Lab Techniques and Equipment:As reflected in the references listed below, our laboratory is interdisciplinary in nature. Thus training in our laboratory capitalizes on a novel integrated strategy that uses an array of techniques to address important problems in cardiac biology. These methods include biochemical techniques such as: enzyme assays, Western blot protein analysis, immunoprecipitations and protein fractionation. We use molecular biology methods the study protein expression including, PCR analysis, Northern blot assays and gene transfection methods to express heterologous proteins in cultured heart cells. We also use single cell methods that provide functional information to complement these molecular approaches including: edge detection video microscopy to measure contractility, single cell voltage clamp electrophysiology, intracellular Ca measurements with fluorescent indicators, and high-resolution confocal Ca2+ imaging.