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O'Rourke Lab

The O’Rourke lab uses an integrated approach to study the biophysics and physiology of cardiac cells in normal and diseased states.

State-of-the-art techniques, including single-channel and whole-cell patch clamp, microfluorimetry, conventional and two-photon fluorescence imaging, and molecular biology are used in studies spanning from the structure and function of single proteins to the intact muscle. Experimental results are compared with simulations of computational models in order to understand the findings in the context of the system as a whole.

These models have continually broken new ground with respect to integrating mitochondrial energetics, Ca2+ dynamics and electrophysiology to provide tools for studying how defective function of one component of the cell can lead to catastrophic effects on whole cell and whole organ function.

Important applications of this powerful approach have led, for example, to new insights about the specific changes in Ca2+ handling, and action potential remodeling in animal models of heart failure. By dissecting out the individual rate constants for Ca2+ uptake by the sarcoplasmic reticulum and the Na+/Ca2+ exchanger of the surface membrane, experimental result were incorporated into quantitative cardiac cell models of heart failure.

Novel information about how changes in intracellular Ca2+ influence the myocyte’s action potential and how competing Ca2+ removal pathways can modify the releasable pool of Ca2+, and consequently muscle contraction, emerged from these studies. More recently, mitochondrial energetics, reactive oxygen species and intracellular ion dynamics have been added to the cell models and 3-dimensional representations of the myocardial syncytium are now possible.

This has allowed Dr. O’Rourke’s group to explore the links between Ca2+, electrical excitability, and energy production with the overall objective being to understand the cellular basis of cardiac arrhythmias, ischemia-reperfusion injury, and sudden death.

Members

Dr. Brian O’Rourke is a Professor in the Division of Cardiology, Department of Medicine of the Johns Hopkins University.

Dr. O’Rourke obtained his undergraduate degree in Biochemistry from The Pennsylvania State University in 1983 and pursued his interest in cardiac muscle function as a graduate student in the Department of Physiology of Thomas Jefferson University in Philadelphia (PhD 1990). His primary advisor there, Dr. Diane Reibel, as an alumnus of the renowned cardiac energetics laboratory of Dr. James Neely, spurred his interest in energy metabolism and its relationship to cardiac function.

In parallel, Dr. O’Rourke worked in the laboratory of Dr. Andrew P. Thomas, whose methodological and theoretical expertise provided invaluable insight into intracellular Ca2+ signaling, mitochondrial metabolism, non-linear dynamics and cellular imaging. These skills were applied to the study of adrenergic signaling in single heart cells using a unique high-speed fluorescence imaging method.

His career at Johns Hopkins began with postdoctoral training in the laboratory of Eduardo Marbán, MD, PhD, under whose mentorship Dr. O’Rourke developed as a skilled cellular electrophysiologist. During this time, Dr. O’Rourke made several important discoveries revealing the close interrelationship between the energetic status of the cell and the electrophysiological and Ca2+ handling properties of the cardiomyocyte. He has continued to pursue this theme throughout his independent research career.

Over the course of his career, Dr. O’Rourke has been most interested in developing cross-disciplinary teams of collaborators with various backgrounds to approach the complex issues involved in understanding the heart as a system, and fortunately, he has been in an environment with like-minded and talented people. Dr. O’Rourke currently directs a Program Project on mitochondrial function in cardiac disease, holds an NIH MERIT award, and is principal investigator on two other grants.

Projects

  • Identifying the specific molecular targets modified by oxidative or ischemic stress and how they affect mitochondrial and whole heart function.
  • Understanding how the molecular details of the heart cell work together to maintain function and how the synchronization of the parts can go wrong. Rational strategies can then be devised to correct dysfunction during the progression of disease through a comprehensive understanding of basic mechanisms.