This Program Project comprises four closely integrated multi-disciplinary projects addressing a common theme of major significance: the molecular and electrophysiologic bases of cell-to-cell communication and impulse propagation and cardiac muscle. In the first project, we propose to study 3-dimensional (3D) cortex-like reentry (scroll waves) as the mechanism of ventricular fibrillation (VF). We use computer modeling and novel optical mapping techniques based on transillumination to determine the mechanisms controlling the dynamics of intramural scroll waves in the ventricles of sheep. We postulate that intramural scroll waves tend to align their rotation axis (filament) with fiber orientation. Since the organization of the fibers across myocardial wall is complex, electrical impulses emanating from such scroll waves result in complex dynamics characteristic of fibrillation. The next project focuses on the role of transmembrane current kinetics in the dynamics of vortices of excitation. The objective is to construct an advanced 3D model of the mouse heart to investigate ionic mechanisms of scroll wave propagation, in the presence of normal and altered ion channel kinetics. Model predictions will be rigorously tested in experiments using transgenic mice lacking (Kv4.2 dominant negative) or over-expressing (Ina-Ca over-expressor) specific integral membrane proteins. Dr. Jalife's project focuses on the consequences of reduced expression of cardiac connexins in impulse propagation and arrhythmias in genetically engineered mice. This project also uses high resolution optical recording techniques.
It aims at elucidating the electrophysiological consequences of lack of connexin43 (Cx43) or Cx40 in the ventricle, His-Purkinje system and atria of the mouse heart. Dr. Delmar's project, we will use molecular and electrophysiological approaches in three different biological systems (Xenopus Laevis oocytes, N2A cells and cardiac neural crest cells) to study gap function regulation and chemical regulation of and its effects on cell behavior. We focus on multimeric channels formed by Cx40 and Cx43 and propose to study chemical regulation on heteromeric connexin interactions, as well as heterodomain interactions. Also, we plan to study whether expressed Cx43 carboxyl terminus (CT) fragments interfere with chemical regulation of connexins. Moreover, a transgenic mouse will be used to determine whether over-expression of the Cx43CT domain leads to functional alterations in cell physiology and organ function. Overall, this highly significant and innovative Program Project addresses fundamental problems in cardiac biology. Achieving our proposed goals should advance the filed, and hopefully lead to diagnostic and therapeutic improvements.
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