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Brian O’Rourke, PhD

Department Affiliations Medicine
Rank Professor
Office Phone 410-614-0034
Lab Phone
Fax 410-502-5055
Email bor@jhmi.edu
SOM Address Room 1060 Ross Research Building
Website
Students

Deepthi Ashok 2013

Research Interests

The goal of the laboratory is to use 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 the gamut from single proteins to the intact animal. Experimental results are compared with computational models in order to understand the findings in the context of the system as a whole. We have also extended this systems biology approach to include multi-omics technologies applied to cardiovascular disease, with the goal of understanding how the transcriptome, proteome, and metabolome contribute to the progression of the disease. We can then focus on targets and pathways for intervention, for example, in heart failure, sudden cardiac death, or ischemia-reperfusion injury.

We have used this approach to determine the specific changes in Ca2+ handling in an animal model 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, we could incorporate the results into a quantitative cardiac cell model. Novel information about how changes in intracellular Ca2+ influence the myocyte’s action potential and how competing Ca2+ removal pathways could modify the releasable pool of Ca2+, and consequently muscle contraction, emerged from these studies. Continuing investigations explore the links mitochondrial Ca2+ dynamics, reactive oxygen species and excitability, with the overall objective being to understand the cellular basis of cardiac arrhythmias and sudden death.

A second major emphasis of the laboratory is to characterize the mechanisms of control and modulation of mitochondrial function. In this regard, we have discovered a number of novel ion channel types on the mitochondrial inner membrane, which influence the energetic state of the mitochondrion. We have shown that some of these mitochondrial channels (e.g., the mitochondrial KATP and KCa2+ channels) play an instrumental role in protecting myocytes from necrotic and apoptotic cell death, while others contribute to mitochondrial dysfunction (e.g., permeability transition pores). On this topic, we are also developing computational models of bioenergetics that have been integrated into the virtual cell model described above, allowing a detailed exploration of the links between metabolism, Ca2+ homeostasis and electrical excitability.

The motivation for all of this work is to understand how all the molecular details of the heart cell work together to maintain function and how things can go wrong. We can then rationally devise ways of correcting dysfunction during the progression of disease using new gene transfer methodologies or specifically targeted pharmacological agents.

Publications

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Research Profile