Control of Local Calcium Signaling in the Heart

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DESCRIPTION (provided by applicant): 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.