Defects in cardiac excitability are the basis for human arrhythmia and sudden cardiac death, a leading cause of mortality in developed countries. Unfortunately, arguably the last major ?game-changing? breakthroughs in electrical cardiomyocyte biology and cardiac signaling for human health were the beta- blocker (discovered in the 1950s) and `ACE' inhibitor (in the 1970s). On the other hand, therapeutic agents to treat disorders of cardiac excitation (arrhythmias) are plagued by limited efficacy and even off-target pro- arrhythmia. Despite a wealth of negative clinical data, excitable cell researchers have largely remained focused on the same paradigm - pharmacological therapies targeting cardiac ion channels. We contend that improved therapies will only arise through a more sophisticated, working understanding of interactions between structural proteins (such as ankyrins), electrical proteins (ion channels, pumps & exchangers) and signaling systems (kinases, phosphatases, oxidases). Our studies discovered that ankyrin and spectrin proteins, previously considered static membrane adapters, play dynamic roles in ion channel, transporter, and signaling protein targeting in ventricular cardiomyocytes. Further, we have learned that these proteins serve as critical central membrane nodes to regulate normal signaling in heart. Finally, and most importantly, we have learned that dysfunction in these pathways results in potentially fatal forms of both congenital and acquired ventricular arrhythmia. Our long-term goal is to discover novel integrated mechanisms for regulating cardiovascular cell excitability and signaling. We have used the informative case of ankyrins and spectrins as a tractable starting point, but propose to rapidly extend these studies to new systems with diverse interacting structure-electrical- signaling systems. Our laboratory has taken an active lead in the identification of new cellular pathways for regulation of cellular excitability based on human clinical, tissue, and genetic data. In addition, we have pushed innovation in the field through the use of physiologically-relevant model systems to study the mechanisms underlying electrical signaling in the complex vertebrate cardiomyocyte. This approach has ultimately culminated in an ability to not only diagnose new forms of potentially fatal arrhythmia, but to design effective patient-selective therapies for these diseases. If successful in obtaining funding from the NHLBI Outstanding Investigator Award, we will continue to pursue scientific studies with the potential to create new, cell-specific insights for improved understanding of cardiac excitability with direct relevance for congenital and acquired human disease.
Defects in cardiac excitability are the basis for human arrhythmia and sudden cardiac death, a leading cause of mortality in developed countries. Our goal is to discover novel integrated mechanisms for regulating cardiovascular cell excitability and signaling. We have used the informative case of ankyrins and spectrins as a tractable starting point, but propose to rapidly extend these studies to new systems with diverse interacting structure-electrical-signaling systems.
|Zhu, Wengen; Wang, Cen; Hu, Jinzhu et al. (2018) Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation. Circulation 138:2682-2697|
|Kempton, Amber; Cefalu, Matt; Justice, Cody et al. (2018) Altered regulation of cardiac ankyrin repeat protein in heart failure. Heliyon 4:e00514|
|Unudurthi, Sathya D; Nassal, Drew; Greer-Short, Amara et al. (2018) ?IV-Spectrin regulates STAT3 targeting to tune cardiac response to pressure overload. J Clin Invest 128:5561-5572|
|Yoo, Shin; Aistrup, Gary; Shiferaw, Yohannes et al. (2018) Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure. JCI Insight 3:|
|He, Beixin Julie; Boyden, Penelope; Scheinman, Melvin (2018) Ventricular arrhythmias involving the His-Purkinje system in the structurally abnormal heart. Pacing Clin Electrophysiol 41:1051-1059|
|Makara, Michael A; Curran, Jerry; Lubbers, Ellen R et al. (2018) Novel Mechanistic Roles for Ankyrin-G in Cardiac Remodeling and Heart Failure. JACC Basic Transl Sci 3:675-689|
|Chung, Jae-Hoon; Martin, Brit L; Canan, Benjamin D et al. (2018) Etiology-dependent impairment of relaxation kinetics in right ventricular end-stage failing human myocardium. J Mol Cell Cardiol 121:81-93|
|Mohler, Peter J; Hund, Thomas J (2017) Novel Pathways for Regulation of Sinoatrial Node Plasticity and Heart Rate. Circ Res 121:1027-1028|
|El Refaey, Mona; Xu, Li; Gao, Yandi et al. (2017) In Vivo Genome Editing Restores Dystrophin Expression and Cardiac Function in Dystrophic Mice. Circ Res 121:923-929|
|Koenig, Sara N; Mohler, Peter J (2017) The evolving role of ankyrin-B in cardiovascular disease. Heart Rhythm 14:1884-1889|
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