Each heartbeat requires the coordination of electrical excitation and mechanical contraction in every heart cell, a process that requires a relatively small amount of calcium (Ca) entering the cell to trigger a much larger release of Ca from the sarcoplasmic reticulum (SR). In healthy hearts, this process of Ca-induced Ca release (CICR) is surprisingly stable despite the fact that it relies on positive feedback. However, mis-regulation of CICR has recently been shown to play a central role in disease states such as heart failure. Although a considerable amount has been learned about how the elementary units of Ca release, Ca sparks, are triggered, very little is known about how these events terminate or whether defective termination plays a role in disease. The goal of this proposal is to investigate fundamental molecular mechanisms by which Ca sparks terminate and how the termination of these events affects the regulation of CICR.
The aims of this proposal will be to perform critical experimental tests that address several fundamental unanswered questions regarding how Ca sparks are triggered and how they terminate. To accomplish the Specific Aims of this proposal, experiments will be performed on single ventricular myocytes isolated from rat and rabbit hearts. Sub-cellular changes in Ca concentration in these cells will be tracked with a fluorescent indicator and a confocal microscope. Computer modeling, based on the Pi's previous work, will be used to interpret data and develop hypotheses. This work will provide fundamental new information about how Ca is regulated in normal hearts. This can provide a foundation for better understanding how Ca can be mis-regulated in disease. This work therefore fits in with the Pi's long term objective of understanding electrical and chemical signaling in healthy and diseased hearts.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076230-04
Application #
7228277
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Przywara, Dennis
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$321,433
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Polakova, Eva; Sobie, Eric A (2013) Alterations in T-tubule and dyad structure in heart disease: challenges and opportunities for computational analyses. Cardiovasc Res 98:233-9

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