Calcium (Ca2+) dependent arrhythmias have been identified as a significant health problem leading to ventricular tachycardia, fibrillation and death. The exact mechanism by which these arrhythmias arise remains a critically important yet vexing problem. We hypothesize that these Ca2+ dependent arrhythmias occur through a process in which a propagating wave of elevated calcium travels through heart cells and thereby activates and entrains electrical activity. The proposals PIs (Lederer, Jafri, and Winslow) will combine state-of- the art computational modeling with novel laboratory experiments in a multi-scale approach to determine how the calcium signaling defect develops and critically test the hypothesis. This systems biology investigation will examine the molecular physiology of cardiac Ca2+ signaling at high temporal and spatial resolution under normal and pathological conditions. It will utilize the unusually powerful approach of specifically examining the molecular pathophysiology of the Ca2+ dependent arrhythmia using the molecular disease, catecholaminergic polymorphic ventricular tachycardia (CPVT) caused by an extremely well-defined process - point mutations of critical Ca2+ regulatory proteins. We will examine how mutations in the calcium release channel (ryanodine receptor type 2, RyR2) and the Ca2+ binding protein, calsequestrin (CASQ2) contribute to Ca2+ dependent arrhythmogenesis. Mouse models of these two arrhythmias will be used to enable advanced cell biology investigations. The work will be made more general by also including an examination of Ca2+ overload arrhythmias in mouse and guinea pig. The planned investigation will encompass multiple scales: from the molecular defect, to cellular Ca2+ dysfunction to tissue arrhythmia using both mathematical modeling and biological experiments. The project will address the following four specific aims: 1) How do Ca2+sparks trigger and sustain calcium waves? 2) How do Ca2+waves propagate from cell to cell? How do Ca2+waves entrain electrical activity? 3) How do specific mutations in RyR2 and CASQ2 affect Ca2+sparks, Ca2+waves and the propagation of Ca2+waves from cell to cell? 4) How does the 3D organization of the heart affect Ca2+ entrained arrhythmogenesis? This work should provide fundamental new understanding of the heart and the role of Ca2+ in electrical dysfunction and arrhythmia and lay the foundation for new therapeutic approaches.

Public Health Relevance

Calcium dependent cardiac arrhythmias have been identified as a significant health problem and a major cause of cardiac death. The proposed work will provide new understanding of the molecular and cellular causes of these heart rhythm disturbances and enable new treatments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105239-02
Application #
8244429
Study Section
Special Emphasis Panel (ZRG1-VH-D (50))
Program Officer
Larkin, Jennie E
Project Start
2011-04-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$969,810
Indirect Cost
$154,551
Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Wescott, Andrew P; Jafri, M Saleet; Lederer, W J et al. (2016) Ryanodine receptor sensitivity governs the stability and synchrony of local calcium release during cardiac excitation-contraction coupling. J Mol Cell Cardiol 92:82-92
Xu, Shan; Cherok, Edward; Das, Shweta et al. (2016) Mitochondrial E3 ubiquitin ligase MARCH5 controls mitochondrial fission and cell sensitivity to stress-induced apoptosis through regulation of MiD49 protein. Mol Biol Cell 27:349-59
Ullah, Ghanim; Ullah, Aman (2016) Mode switching of Inositol 1,4,5-trisphosphate receptor channel shapes the Spatiotemporal scales of Ca(2+) signals. J Biol Phys 42:507-524
Zhao, Claire Y; Greenstein, Joseph L; Winslow, Raimond L (2016) Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network. J Mol Cell Cardiol 91:215-27
Foteinou, Panagiota T; Greenstein, Joseph L; Winslow, Raimond L (2015) Mechanistic Investigation of the Arrhythmogenic Role of Oxidized CaMKII in the Heart. Biophys J 109:838-49
Walker, Mark A; Kohl, Tobias; Lehnart, Stephan E et al. (2015) On the Adjacency Matrix of RyR2 Cluster Structures. PLoS Comput Biol 11:e1004521
Zhao, Guiling; Li, Tianyu; Brochet, Didier X P et al. (2015) STIM1 enhances SR Ca2+ content through binding phospholamban in rat ventricular myocytes. Proc Natl Acad Sci U S A 112:E4792-801
Williams, George S B; Boyman, Liron; Lederer, W Jonathan (2015) Mitochondrial calcium and the regulation of metabolism in the heart. J Mol Cell Cardiol 78:35-45
Yang, Pei-Chi; Jafri, M Saleet (2015) The Phase Lag between Agonist-Induced Oscillatory Ca(2+) and IP3 Signals Does Not Imply Causality (December 2015). Calcium Signal (St Clara) 2:1-10
Limbu, Sarita; Hoang-Trong, Tuan M; Prosser, Benjamin L et al. (2015) Modeling Local X-ROS and Calcium Signaling in the Heart. Biophys J 109:2037-50

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