Cardiac hypertrophy is the result of complex genetically predetermined electrical and mechanical remodeling? programs in response to mechanical and neurohumoral stimuli. Ca plays a pivotal role in the activation and? regulation of several hypertrophy transcription pathways, while Ca signaling itself undergoes profound? changes in hypertrophy (Hyp) and heart failure (HF), including significant contributions from InsP3-dependent? Ca release.? The specific aims of the proposed study are:? 1) characterize the role of InsP3-dependent Ca signaling for excitation-contraction coupling (ECC) in? atrial and ventricular myocytes under physiological conditions and in Hyp/HF.? 2) test the hypothesis that InsP3-dependent Ca release facilitates arrhythmogenic Ca signals (SR Ca? overload, Ca waves, Ca alternans, enhanced Ca spark frequency) and changes of membrane potential? (early (EAD) and delayed (DAD) afterdepolarizations, spontaneous action potentials (APs) and? electrical alternans) in Hyp/HF ventricular myocytes.? 3) identify the cellular and subcellular Ca signaling pathways and spatio-temporal [Ca], patterns? relevant for nuclear Ca/calmodulin/calcineurin-dependent NFAT translocation which initiate gene? transcription and gene expression in cardiac Hyp and HF.? To achieve these aims a multitude of experimental techniques will be used: high resolution Ca imaging by? laser scanning confocal microscopy in single cardiac myocytes, novel FRET(CFP/YFP) fluorescent InsP3? sensors to study the cellular and subcellular dynamics of InsP3, whole-cell voltage clamp techniques to study? membrane currents and membrane potential changes, and molecular biological and pharmacological tools to? manipulate the InsP3/Ca/calmodulin/clacineurin/NFAT signaling cascade. Furthermore, several animal/cell? models will be used including wild-type mouse and rabbit, hypertrophy mouse, InsPa receptor knockout? mouse and heart failure rabbit.? The proposed research will generate fundamental new information on the roles of InsP3R-dependent Ca? signaling in cardiac myocytes during ECC, in arrhythmogenesis, electrophysiological changes and nuclear? transcription signaling in normal, Hyp and HF cardiac myocytes.?
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