This Program Project comprises four closely integrated multidisciplinary projects addressing questions from bench to bedside, with a common theme of major significance: the molecular and electrophysiologic bases of cell-to-cell communication and impulse propagation in cardiac muscle. In Project 1. we propose to translate fundamental knowledge on mechanisms of atrial fibrillation (AF) into an understanding of AF in humans. We will investigate the means by which electrical activity gives rise to the different spatial organization of frequency and regularity in the atria of patients presenting paroxysmal versus persistent AF. Our hypothesis is that the distribution of local activation frequency and degree of irregularity in those patients is the result of fibrillatory conduction of waves emanating from AF drivers localized at sites of highest frequency, and that such sites are different in the two groups of patients. Project 2_focuses on the role of potassium channels in the control of frequency dependent cardiac excitation, intermittent wave propagation and fibrillatory conduction. Our main focus is the manner in which the strong inward rectifier Kir2.1 (KCNJ2) and the delayed rectifier HERG (KCHN2) and KyLQT1 (KCNQ1)/mink (KCNE1) modify the ability of cardiac electrical waves to propagate through non-homogeneous cardiac muscle during complex arrhythmias such as ventricular fibrillation. Project 3 focuses on the characterization of the function and regulation of cardiac gap junctions in a mouse line where the Cx43 molecule has been replaced with a truncation mutant lacking the carboxyl terminal (CT) domain. Our experiments will test the hypothesis that the integrity of the CT domain is essential for the regulation of native cardiac gap junctions and will assess whether this regulation plays a key role in specific morphological and electrophysiological changes that follow myocardial ischemia and infarction. In Project 4. we will characterize the interaction of Cx43CT with a family of connexin-interacting peptides and the consequences of this interaction on channel function. We will utilize a combination of nuclear magnetic resonance, surface plasmon resonance, patch clamp analysis and general cell and molecular biology approaches. Here, our objective is to apply the knowledge acquired through structure-function studies of Cx43 regulation to the development of pharmacophores able to modify gap junction regulation and function. Overall, this highly significant and innovative Program Project addresses fundamental problems in cardiac biology and clinical electrophysiology. Achieving our proposed goals should advance the field, and hopefully lead to diagnostic and therapeutic improvements.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL039707-19
Application #
7691301
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Przywara, Dennis
Project Start
1997-05-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
19
Fiscal Year
2009
Total Cost
$1,825,445
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ponce-Balbuena, Daniela; Guerrero-Serna, Guadalupe; Valdivia, Carmen R et al. (2018) Cardiac Kir2.1 and NaV1.5 Channels Traffic Together to the Sarcolemma to Control Excitability. Circ Res 122:1501-1516
Rodrigo, M; Climent, A M; Liberos, A et al. (2017) Minimal configuration of body surface potential mapping for discrimination of left versus right dominant frequencies during atrial fibrillation. Pacing Clin Electrophysiol 40:940-946
Rodrigo, Miguel; Climent, Andreu M; Liberos, Alejandro et al. (2017) Highest dominant frequency and rotor positions are robust markers of driver location during noninvasive mapping of atrial fibrillation: A computational study. Heart Rhythm 14:1224-1233
Quintanilla, Jorge G; Pérez-Villacastín, Julián; Pérez-Castellano, Nicasio et al. (2016) Mechanistic Approaches to Detect, Target, and Ablate the Drivers of Atrial Fibrillation. Circ Arrhythm Electrophysiol 9:e002481
Takemoto, Yoshio; Ramirez, Rafael J; Yokokawa, Miki et al. (2016) Galectin-3 Regulates Atrial Fibrillation Remodeling and Predicts Catheter Ablation Outcomes. JACC Basic Transl Sci 1:143-154
Filgueiras-Rama, David; Jalife, José (2016) STRUCTURAL AND FUNCTIONAL BASES OF CARDIAC FIBRILLATION. DIFFERENCES AND SIMILARITIES BETWEEN ATRIA AND VENTRICLES. JACC Clin Electrophysiol 2:1-3
Pedrón-Torrecilla, Jorge; Rodrigo, Miguel; Climent, Andreu M et al. (2016) Noninvasive Estimation of Epicardial Dominant High-Frequency Regions During Atrial Fibrillation. J Cardiovasc Electrophysiol 27:435-42
Herron, Todd J; Rocha, Andre Monteiro Da; Campbell, Katherine F et al. (2016) Extracellular Matrix-Mediated Maturation of Human Pluripotent Stem Cell-Derived Cardiac Monolayer Structure and Electrophysiological Function. Circ Arrhythm Electrophysiol 9:e003638
Guillem, María S; Climent, Andreu M; Rodrigo, Miguel et al. (2016) Presence and stability of rotors in atrial fibrillation: evidence and therapeutic implications. Cardiovasc Res 109:480-92
Willis, B Cicero; Pandit, Sandeep V; Ponce-Balbuena, Daniela et al. (2016) Constitutive Intracellular Na+ Excess in Purkinje Cells Promotes Arrhythmogenesis at Lower Levels of Stress Than Ventricular Myocytes From Mice With Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation 133:2348-59

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