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.
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