IPaR-dependent Ca release plays an important role for a wide variety of cardiac functions, including modulation of excitation-contraction coupling (ECC), generation of arrhythmia, modulation of mitochondrial function and regulation of Ca-dependent transcription factors in hypertrophy and hear failure. The overall goal of the proposed study is to 1) identify the mechanisms of IPsR-dependent Ca signaling for diastolic and systolic function, 2) determine the relationship between IPaR-dependent Ca release, mitochondrial Ca uptake and its effect on mitochondrial function, and 3) define the Ca-dependent mechanisms of isoform- and tissuespecific regulation of the hypertrophy transcription factor NFAT.
The specific aims are: 1) test the hypothesis that IP3 receptor (IP3R)-dependent Ca release modulates diastolic (SR Ca leak) and systolic (positive inotropic and proarrhythmic effects) Ca signaling in normal adult myocytes and in cardiac hypertrophy and heart failure; 2) test the hypothesis that IPsR-dependent Ca release enhances mitochondrial Ca uptake and mitochondrial Ca-dependent functions (Ca-dependent hydrogenases and metabolic function;opening of the permeability transition pore;nitric oxide (NO) and ROS production by mitochondrial NOS, leading to altered cellular redox state); 3) identify Ca signaling pathways relevant for the activation of the transcription factor NFAT that initiates hypertrophic remodeling processes, and test the hypothesis that Ca-dependent regulation of NFAT is isoform- (NFATcl vs. NFATc3), tissue- (atrial vs. ventricle) and disease state- (normal vs. heart failure) specific and modulated by the redox state of the cell. To achieve these aims a multitude of experimental techniques will be used: high resolution imaging by laser scanning confocal microscopy in single myocytes to measure whole cell and subcellular [Ca]i, [Cajmito and [Ca]sR, whole-cell voltage and current clamp techniques, subcellular photolysis of caged Ca, adenoviral gene-transfer, and pharmacological manipulation of Ca transport and buffering. Experiments will be conducted on adult myocytes from wild-type mouse and rabbit, heart failure rabbit, and transgenic mouse models. The proposed research will provide fundamental new information on the cellular mechanism of Ca signaling relevant to the understanding of cardiac hypertrophy and failure.

Public Health Relevance

Cardiovascular diseases, including cardiac hypertrophy and failure, dre among the leading causes of morbidity and mortality, and are responsible for a significant portion of health related costs. This study seeks to investigate, at the cellular level, the specific disturbances in cellular calcium homeostasis of the diseased heart that ultimately result in failing heart function, and to elucidate the mechanisms and signaling pathways that result in the structural and functional changes typical for the hypertrophic and failing heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL080101-09
Application #
8697101
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
9
Fiscal Year
2014
Total Cost
$472,590
Indirect Cost
$65,580
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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