Translational Control of Cardiac Excitability

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PROJECT SUMMARY/ABSTRACT The regular beating of the heart requires the orchestrated expression of ion channel ensembles specific for ventricular repolarization, pacemaking, conduction and other functions. Recent progress establishes a new way in which channel expression is coordinated. The central hypothesis of this proposal is that a “microtranslatome” of interacting mRNA species encodes functionally related proteins, such as those producing the ventricular action potential. These ion channels assemble cotranslationally into macromolecular complexes that govern higher-order cardiac excitability. The aims of the proposal are to resolve components of cotranslational complexes mediating cardiac repolarization using single-molecule fluorescence in situ hybridization combined with protein immunofluorescence (smFISH/IF) in both embryonic (iPSC) and adult cardiomyocytes. Hypotheses regarding the composition, stoichiometry and cellular localization of these complexes will be tested. Whether such complexes regulate other cardiac functions, such as pacemaking, will be determined. Mechanisms mediating mRNA association, such as candidate RNA binding proteins (RBPs) identified with affinity-capture mass spectrometry, and direct mRNA interactions, will be resolved. These studies are expected to illuminate new mechanisms by which cardiac excitability is controlled and identify novel targets for disease and therapeutic development.