Cardiac arrhythmias remain a major cause of death and disability, affecting both genders and all age groups. Treatment is mostly empirical, with unpredictable outcomes in many cases. The disease processes that lead to irregular heart rhythms often involve alterations in the molecular structure and function of ion channels, which constitute the elementary """"""""building blocks"""""""" of the cardiac excitatory process. These changes can be due to mutations, remodeling by disease processes and/or environmental factors, or unwanted effects of drugs. Promising new approaches to the treatment of cardiac arrhythmias and prevention of sudden cardiac death, including molecular and gene therapy and rational drug design, require knowledge of processes and mechanisms at the molecular level of ion-channel proteins and their integrated effects on whole-cell excitation. The overall objective of the proposed project is to provide mechanistic understanding of the relationships between the dynamic molecular structure of cardiac ion- channel proteins during their gating process and their function as charge carriers during the whole-cell action potential (AP). Processes to be studied include the alteration of the channel structure-function properties by mutations and their modulation by cellular signaling pathways (?- adrenergic and CaMKII). Specifically, we will focus on the slow delayed rectifier K+ channel, IKs, and its role in AP repolarization and arrhythmogenic repolarization abnormalities. The approach is based on computational biology methods (combination of molecular dynamics simulations and models of cardiac cell electrophysiology) together with experimental data. ? Specific aims are: (1) To construct a structural molecular model of IKs by incorporating its ?- subunit (KCNE1) into the -subunit (KCNQ1) model that we have developed previously, and to study the functional consequences of KCNE1 co-assembly with KCNQ1 in terms of channel activation gating, the macroscopic IKs current, and the whole-cell AP, including effects of clinically occurring mutations in KCNE1. (2) To study at the molecular level the mechanism of IKs regulation by ?-adrenergic stimulation and explain its effects on IKs current and the whole-cell AP, including consequences of clinical mutations that alter this regulation.

Public Health Relevance

Cardiac arrhythmias are a major cause of death and disability, with estimated 400,000 cases of sudden death annually in the US (7 million worldwide) and many more cases of severely compromised quality of life. These cardiac rhythm disorders affect both genders and all age groups. The proposed studies are aimed at elucidating molecular processes and mechanisms that underlie irregular heart rhythms, in order to provide a rational basis for the development of mechanism-based strategies for improved diagnosis, prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL049054-21A1
Application #
8627954
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
1993-02-01
Project End
2017-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
21
Fiscal Year
2014
Total Cost
$342,000
Indirect Cost
$117,000
Name
Washington University
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Ramasubramanian, Smiruthi; Rudy, Yoram (2018) The Structural Basis of IKs Ion-Channel Activation: Mechanistic Insights from Molecular Simulations. Biophys J 114:2584-2594
Xu, Jiajing; Rudy, Yoram (2018) Effects of ?-subunit on gating of a potassium ion channel: Molecular simulations of cardiac IKs activation. J Mol Cell Cardiol 124:35-44
Andrews, Christopher M; Srinivasan, Neil T; Rosmini, Stefania et al. (2017) Electrical and Structural Substrate of Arrhythmogenic Right Ventricular Cardiomyopathy Determined Using Noninvasive Electrocardiographic Imaging and Late Gadolinium Magnetic Resonance Imaging. Circ Arrhythm Electrophysiol 10:
Rudy, Yoram (2017) Noninvasive ECG imaging (ECGI): Mapping the arrhythmic substrate of the human heart. Int J Cardiol 237:13-14
Lee, Hsiang-Chun; Rudy, Yoram; Liang, Hongwu et al. (2017) Pro-arrhythmogenic Effects of the V141M KCNQ1 Mutation in Short QT Syndrome and Its Potential Therapeutic Targets: Insights from Modeling. J Med Biol Eng 37:780-789
Zhang, Junjie; Hocini, Mélèze; Strom, Maria et al. (2017) The Electrophysiological Substrate of Early Repolarization Syndrome: Noninvasive Mapping in Patients. JACC Clin Electrophysiol 3:894-904
Nekouzadeh, Ali; Rudy, Yoram (2016) Conformational changes of an ion-channel during gating and emerging electrophysiologic properties: Application of a computational approach to cardiac Kv7.1. Prog Biophys Mol Biol 120:18-27
Vijayakumar, Ramya; Vasireddi, Sunil K; Cuculich, Phillip S et al. (2016) Methodology Considerations in Phase Mapping of Human Cardiac Arrhythmias. Circ Arrhythm Electrophysiol 9:
Zhang, Junjie; Cooper, Daniel H; Desouza, Kavit A et al. (2016) Electrophysiologic Scar Substrate in Relation to VT: Noninvasive High-Resolution Mapping and Risk Assessment with ECGI. Pacing Clin Electrophysiol 39:781-91
Rudy, Yoram; Lindsay, Bruce D (2015) Electrocardiographic imaging of heart rhythm disorders: from bench to bedside. Card Electrophysiol Clin 7:17-35

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