In Person Seminar: Nanocardiology: A Microscopy-Driven Approach to Cardiac Biology and Physiology

About this Seminar

 A growing body of evidence indicates that cardiac biology and physiology at cellular through organ scales are governed by the action of proteins organized within nanodomains with specialized ultrastructural properties. Importantly, multiple phenomena have been identified, such as ephaptic coupling and excitation-contraction coupling, whose function in health and dysfunction in disease cannot be predicted without accounting for the makeup and behavior of nanodomains. Thus, Dr. Veeraraghavan's laboratory’s investigative approach is grounded in high resolution structural and functional imaging, which is complemented by nanoelectrophysiology (Prez Radwański), functional imaging (Sándor Györke) and computational modeling (Seth Weinberg). Dr. Veeraraghavan will present results from three ongoing projects to illustrate how this multi-pronged approach is enabling us to take on biological and physiological questions ranging from basic science to translational.

1) The nuts and bolts of cardiac impulse propagation: Cardiac myocytes are electrically coupled via highly specialized and heterogeneous structures called intercalated disks. Using his lab's novel indirect correlative light and electron microscopy (iCLEM) approach, Dr. Veeraraghavan's research team is compiling the first-ever quantitative picture of intercalated disks in healthy, experimentally perturbed and diseased hearts including ultrastructural and molecular organization properties from nano- through micro-scales. These data are incorporated into computational models of cardiac impulse propagation to predict structure-function relationships, which are then verified through functional experiments (optical mapping). Using this approach, the lab is uncovering hitherto unappreciated aspects of intercalated disk organization and their roles in modulating cardiac impulse propagation via ephaptic coupling, self-attenuation and other nanoscale mechanisms.

2) Multiscale arrhythmia mechanisms in calmodulinopathy: The D96V mutation in calmodulin is associated with severe APD prolongation, consequent long QT, and triggered arrhythmias. Although this mutation was shown to pathologically enhance the L-type Ca2+ current, that effect was insufficient to explain the observed arrhythmogenic impacts. By combining structural (STORM single molecule localization microscopy) and functional (scanning ion conductance microscopy-guided ‘smart’ patch clamp) with molecular through in vivo scale approaches,  Dr. Veeraraghavan has uncovered how this defect in calmodulin dysregulates NaV1.6 neuronal sodium channel inactivation and structural organization along cardiomyocyte transverse tubules to promote pro-arrhythmic Na+/Ca2+ mishandling. Importantly, the lab is developing and translating novel antiarrhythmic therapies designed to selectively and safely target NaV1.6.

3) Distributed protein synthesis in cardiac myocytes: It has long been thought that membrane proteins in cardiac myocytes must be synthesized in perinuclear rough endoplasmic reticulum before being trafficked to sites of deployment. Using single molecule RNA visualization and spatial image analysis, Dr. Veeraraghavan and his lab have discovered that some membrane proteins (eg. connexin43) follow this canonical scheme whereas others (eg. NaV1.5, RyR2) are synthesized on-demand at sites of deployment from local mRNA pools provided by microtubule trafficking. Furthermore, the lab is now learning that mRNA trafficking and distributed protein synthesis enable concurrent synthesis of key ion channels (NaV1.5, CaV1.2) and their regulators (CaM) within microtranslatomes localized to specific myocyte regions.

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