The CRCIF was established to foster collaborative efforts aimed at elucidating the role of inte...rmediate filaments (IFs) in the heart. Intermediate filaments constitute a class of cytoskeletal proteins in metazoan cells, however, different from actin microfilaments and tubulin microtubules, their function in cardiac cells is poorly understood. Unique from the other two components of the cytoskeleton, IFs are formed by cell type-specific proteins. Desmin is the main component of the IFs in the cardiac myocytes. We measured the consistent induction of desmin post-translational modifications (PTMs, such as phosphorylation, etc.) in various clinical and experimental models of heart failure. Therefore, one of our main focuses is to determine the contribution of desmin PTMs to the development of heart failure in different animal and clinical models.

Active Projects:

• Quantification of desmin PTM-forms in different forms of heart failure at the peptide level using mass spectrometry
• Functional assessment of the role of desmin PTMs in heart failure development using single site mutagenesis and biophysical methods
• Molecular characterization of desmin preamyloid oligomers using mass spectrometry, in vitro and in vivo imaging
• Assessment of the diagnostic and pharmacological value of desmin PTMs in heart failure development view more

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

Research in our lab has incorporated 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. By understanding the links between Ca2+, electrical excitability and energy production, we hope to understand the cellular basis of cardiac arrhythmias, ischemia-reperfusion injury, and sudden death.

We use state-of-the-art techniques, including single-channel and whole-cell patch clamp, microfluorimetry, conventional and two-photon fluorescence imaging, and molecular biology to study 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.

Ongoing studies in our lab are focused on identifying the specific molecular targets modified by oxidative or ischemic stress and how they affect mitochondrial and whole heart function.

The motivation for all of the work is to understand
• 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.

Brian O’Rourke, PhD, is a professor in the Division of Cardiology and Vice Chair of Basic and Translational Research, Department of Medicine, at the Johns Hopkins University. view more