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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.