The overall goal of this application is to test the subcellular signaling domains and specific molecular targets for calmodulin kinase II (CaMKII) in heart. Work during the previous funding interval has added significantly to a growing body of evidence showing CaMKII contributes to heart failure and arrhythmias. Studies in this proposal will take advantage of new transgenic mice generated in our laboratory with nuclear and cytoplasmic membrane-targeted CaMKII inhibition. We will also use other mice and dominant-negative constructs to genetically replace CaMKII-targeted residues on key calcium homeostatic proteins. We have evidence that challenges the prevailing paradigm that nuclear CaMKII is preeminent for regulating gene transcription. Our findings suggest CaMKII signaling in cytoplasm crosstalks to the nucleus, and we hypothesize nuclear CaMKII signaling affects excitation contraction coupling and arrhythmias. Experiments to understand if nuclear and/or cytoplasmic CaMKII actions affect for myocyte enhancer factor 2 (MEF2) regulated gene programs will use novel in vivo, cellular and molecular approaches to dissect the effects of CaMKII on MEF2 activity. The following Specific Aims will be used: 1. Test the effects of membrane-targeted and nuclear-targeted CaMKII inhibition on myocardial physiology and as protection against structural heart disease in vivo. 2. Determine the cellular and molecular targets for cytoplasmic CaMKII signaling in cardiomyocyte physiology and disease. 3. Dissect the cellular and molecular signaling pathways for beta adrenergic receptor activation of MEF2 signaling in heart. RELEVENCE. This research is directed toward solving a major public health problem. It is estimated that ~400,000 Americans die annually from sudden cardiac death. Most of these patients have a history of myocardial infarction and heart failure. Targeting these pathways with drugs may reduce suffering in these patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Przywara, Dennis
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
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University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
Zip Code
Anderson, Mark E; Ray, Stuart C (2017) It's 10 pm; Do You Know Where Your Data Are? Data Provenance, Curation, and Storage. Circ Res 120:1551-1554
Morris, Angie S; Sebag, Sara C; Paschke, John D et al. (2017) Cationic CaMKII Inhibiting Nanoparticles Prevent Allergic Asthma. Mol Pharm 14:2166-2175
Sebag, Sara C; Koval, Olha M; Paschke, John D et al. (2017) Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma. JCI Insight 2:e88297
Qu, Jingjing; Do, Danh C; Zhou, Yufeng et al. (2017) Oxidized CaMKII promotes asthma through the activation of mast cells. JCI Insight 2:e90139
Feng, Ning; Anderson, Mark E (2017) CaMKII is a nodal signal for multiple programmed cell death pathways in heart. J Mol Cell Cardiol 103:102-109
Unudurthi, Sathya D; Wu, Xiangqiong; Qian, Lan et al. (2016) Two-Pore K+ Channel TREK-1 Regulates Sinoatrial Node Membrane Excitability. J Am Heart Assoc 5:e002865
Takanari, Hiroki; Bourgonje, Vincent J A; Fontes, Magda S C et al. (2016) Calmodulin/CaMKII inhibition improves intercellular communication and impulse propagation in the heart and is antiarrhythmic under conditions when fibrosis is absent. Cardiovasc Res 111:410-21
Sommese, Leandro; Valverde, Carlos A; Blanco, Paula et al. (2016) Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca(2+) release events in a rodent model of early stage diabetes: The arrhythmogenic substrate. Int J Cardiol 202:394-406
Wu, Yuejin; Valdivia, H├ęctor H; Wehrens, Xander H T et al. (2016) A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca2+ Clock. Circ Arrhythm Electrophysiol 9:e003180
Habecker, Beth A; Anderson, Mark E; Birren, Susan J et al. (2016) Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease. J Physiol 594:3853-75

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