Ca2+ plays a pivotal role in both excitation contraction-coupling (ECC) and activation of signaling pathways in the myocardium. However, it remains a mystery how Ca2+-dependent signaling pathways are activated in myocytes given the overwhelming cytosolic Ca2+ concentrations that are achieved to mediate contraction. One possibility is that specialized pools of Ca2+ have evolved that are spatially distinct from the cytoplasmic Ca2+ transient thereby generating a restricted signaling microdomain. Another possibility that will explored here is that global changes in diastolic Ca2+ Is a primary means of driving the cardiac hypertrophic response and ensuing heart failure, such as through calcineurin-NFAT signaling. Moreover, heart failure is often associated with elevations in total intracellular Na+ levels in adult myocytes. This elevation in Na* can secondarily drive Ca2+ elevations through effects on NCX1. Here we will examine the hypothesis that elevations in Na+ can enhance the cardiac hypertrophic response and disease by secondarily enhancing diastolic Ca2+ levels. To examine this hypothesis in Specific Aim#1 we will generate transgenic mice with enhanced Na* influx, while in Specific Aim #2 we will generate and analyze transgenic and gene-targeted that are manipulated for NCX1 and NKA (Na+ /K+ ATPase). When coupled with careful measurements of intracellular Na and Ca2+ , these first 2 aims will determine if and how diastolic Ca2+ programs hypertrophy through calcineurin-NFAT signaling in the heart. Finally, Specific Aim #3 will investigate the role that the mitochondrial permeability transition pore (MPTP) plays in regulating mitochondrial Ca2+ and propensity toward cardiomyopathy.

Public Health Relevance

of this application is rooted in the fundamental issue of how Ca2+ signaling pathways are controlled in the heart, which is of major medical importance considering the centrality that PKCs, CaMKll, and calcineurin play in controlling pathologic remodeling and heart failure. A better understanding of how Ca2+ regulates both contraction and signaling in a contractile cell, such as a cardiac myocyte, could reveal microdomain regulatory mechanisms that control hypertrophy.

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National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of California Davis
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