The overall emphasis of this renewal application is to understand the molecular pathways that control cardiac hypertrophy and homeostasis. Specifically we propose to continue our investigation of calcineurin-NFAT signaling in the heart as a regulatory of pathologic hypertrophy, but also baseline function. We will continue to investigate the signaling relationships that underlie calcineurin's hypertrophic functionality in the heart, with an emphasis on characterizing novel interacting partners with known regulatory implications. Thus we hypothesize that calcineurin-NFAT signaling are critical mediators of cardiac disease responsiveness through highly integrated complexes with other signaling effectors. Indeed, our preliminary data shows a large number of novel signaling effectors that interact with calcineurin in programming the hypertrophic response, and these will be characterized here. We will also investigate a number of novel hypotheses related to non-hypertrophic functions of calcineurin, as well as continue our analysis of hypertrophic regulatory mechanisms. Finally, this renewal application will also attempt to address the source or microdomain of Ca2+ that activates calcineurin signaling in the heart through an in depth and mechanistic assessment of several channels and Ca2+ regulatory proteins. Thus, we hypothesize that select microdomains associated with specific Ca2+ channels can directly communicate with calcineurin outside of contractile Ca2+, thus regulating the hypertrophic response. To examine these various hypotheses we propose 2 distinct but functionally inter-related Specific Aims. We have observed that mice lacking all calcineurin from the heart die for unknown reasons and so very poor ventricular performance.
Specific Aim #1 will evaluate the function of RCAN (formerly known as MCIP) proteins in modulating calcineurin-NFAT signaling, as well as in promoting calcineurin interaction with novel targets in the heart through higher-order complexes. For example, we have determined that RCAN1 directly interacts with TAB2 in generating a novel signaling circuit that allows TAK1 and calcineurin to co-regulate one another in programming the hypertrophy response. Characterization of such novel interactions might suggest other critical functions of calcineurin in the heart, possibly explaining why it is required for viability.
Specific aim #2 will examine the source of Ca2+ that communicates with calcineurin in facilitating its activity in the heart, distinct from total contractile Ca2+. Specifically, we will examine the ability of L-type Ca2+ channels, T-type channels, TRPC channels, and the IP3 receptor to directly communicate with calcineurin by providing a highly local Ca2+ signal outside of excitation-contraction coupling. Thus, the current application will attempt to address the most salient issues and remaining frontiers associated with calcineurin-NFAT signaling in the heart.

Public Health Relevance

This renewal application will continue to investigate the function of a calcium-sensitive signaling pathway in the heart as regulator of hypertrophy and disease. The myocardium can hypertrophy in response to injury, changes in workload, or increases in wall stress. While hypertrophy can initially be a compensatory response that temporarily augments cardiac output, prolonged hypertrophy can be deleterious and eventually leads to heart failure and/or sudden death. In response to hypertrophic stimuli, a fundamental reprogramming occurs within the adult cardiomyocyte that results in the expression of genes encoding fetal protein isoforms. This fundamental reprogramming of gene expression occurs through activation of membrane bound receptors (autocrine or paracrine) that in turn activate second messenger systems and intracellular signaling cascades such as PKC, MAPK, and calcineurin. This application will determine how calcineurin functions to bridge signals from outside the cell to modulation of intracellular physiology and changes in gene expression in determining disease responsiveness. An elucidation of these regulatory relationships surrounding calcineurin is of considerable disease relevance.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-C (02))
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Adhikari, Bishow B
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Cincinnati Children's Hospital Medical Center
United States
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Singh, Sonia R; Robbins, Jeffrey (2018) Desmin and Cardiac Disease: An Unfolding Story. Circ Res 122:1324-1326
Khalil, Hadi; Maillet, Marjorie; Molkentin, Jeffery D (2017) Spatial Gene Profiling in the Ischemic Heart: Fibroblasts Put on Their SOX. Circulation 136:1410-1411
Robbins, Jeffrey (2017) Oliver Smithies, DPhil: 1925-2017. Circ Res 120:1535-1536
Kanisicak, Onur; Vagnozzi, Ronald J; Molkentin, Jeffery D (2017) Identity Crisis for Regenerative Cardiac cKit+ Cells. Circ Res 121:1130-1132
Karch, Jason; Molkentin, Jeffery D (2015) Regulated necrotic cell death: the passive aggressive side of Bax and Bak. Circ Res 116:1800-9
Kwong, Jennifer Q; Lu, Xiyuan; Correll, Robert N et al. (2015) The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart. Cell Rep 12:15-22
Correll, Robert N; Goonasekera, Sanjeewa A; van Berlo, Jop H et al. (2015) STIM1 elevation in the heart results in aberrant Ca²? handling and cardiomyopathy. J Mol Cell Cardiol 87:38-47
Wang, Xuejun; Robbins, Jeffrey (2014) Proteasomal and lysosomal protein degradation and heart disease. J Mol Cell Cardiol 71:16-24
Kwong, J Q; Davis, J; Baines, C P et al. (2014) Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ 21:1209-17
Molkentin, Jeffery D (2013) Parsing good versus bad signaling pathways in the heart: role of calcineurin-nuclear factor of activated T-cells. Circ Res 113:16-9

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