Defects in cardiac excitability are the basis for human arrhythmia and sudden cardiac death, a leading cause of mortality in developed countries. Recent findings demonstrate a new paradigm for human arrhythmia based on gene mutations that affect the expression/subcellular localization of cardiac ion channels and transporters. Human type 4 long QT syndrome (LQT4) results from loss-of-function mutations in the membrane adapter ankyrin-B (AnkB). Subjects with LQT4, and mice with reduced AnkB expression display similar complex cardiac phenotypes including atrial, ventricular, conduction defects, and risk of sudden cardiac death. However, the molecular identities of AnkB polypeptides, scope of AnkB expression in specialized cardiac cells, and cellular role(s) for AnkB polypeptides for cardiac excitability remain critical, yet unanswered questions. Moreover, the mechanisms underlying AnkB regulation in normal heart, and dysfunction in human arrhythmia remain unsolved. The long-term objective of this research proposal is to understand the molecular basis for AnkB function in the heart. We hypothesize that coordinate dysfunction of AnkB polypeptides throughout the heart create the complex phenotype of human type 4 long QT syndrome due to defects in ion channel/transporter trafficking and membrane stability.
The specific aims are to: 1) Characterize the expression and subcellular distribution of AnkB isoforms in diverse excitable cell types of heart. 2) Define the cellular role(s) of AnkB for ion channel/transporter trafficking and localization in adult cardiomyocytes using recently developed lentiviral techniques. 3) Characterize the mechanisms underlying AnkB regulation in heart, and determine how human AnkB loss-of-function mutations associated with fatal arrhythmia affect this regulation. The cellular pathways underlying ion channel and transporter targeting, localization, and stability in cardiomyocytes are essentially unknown but present an exciting new target for future cardiac therapies. We propose to use recently developed expression techniques to elucidate the molecular mechanisms underlying AnkB-dependent cellular pathways for ion channel and transporter targeting, localization, and stability in the physiological context of the primary cardiomyocyte. It is anticipated that this information will advance understanding of mechanisms underlying AnkB-based human fatal human arrhythmia as well as acquired cardiac arrhythmias associated with abnormal Ca2+ homeostasis, and begin to define potential future molecular targets for the regulation of cellular excitability.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084583-05
Application #
7898660
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Przywara, Dennis
Project Start
2006-09-01
Project End
2011-02-21
Budget Start
2010-08-01
Budget End
2011-02-21
Support Year
5
Fiscal Year
2010
Total Cost
$152,831
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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
Li, Ning; Hansen, Brian J; Csepe, Thomas A et al. (2017) Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure. Sci Transl Med 9:
Koenig, Sara N; Mohler, Peter J (2017) The evolving role of ankyrin-B in cardiovascular disease. Heart Rhythm 14:1884-1889
Huq, A J; Pertile, M D; Davis, A M et al. (2017) A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation. Heart Lung Circ 26:612-618
Csepe, Thomas A; Zhao, Jichao; Sul, Lidiya V et al. (2017) Novel application of 3D contrast-enhanced CMR to define fibrotic structure of the human sinoatrial node in vivo. Eur Heart J Cardiovasc Imaging 18:862-869
Swayne, Leigh Anne; Murphy, Nathaniel P; Asuri, Sirisha et al. (2017) Novel Variant in the ANK2 Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome. Circ Cardiovasc Genet 10:
Musa, Hassan; Murphy, Nathaniel P; Curran, Jerry et al. (2016) Common human ANK2 variant confers in vivo arrhythmia phenotypes. Heart Rhythm 13:1932-40
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
Adelman, Sara; Daoud, Georges; Mohler, Peter J (2016) Strategies for Risk Analysis and Disease Classification in Atrial Fibrillation. J Cardiovasc Electrophysiol 27:1271-1273
Li, Ning; Csepe, Thomas A; Hansen, Brian J et al. (2016) Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart. Circulation 134:486-98

Showing the most recent 10 out of 113 publications