This training grant is designed to provide the principal investigator (Pl) with the necessary didactic training and laboratory experience to become an independent biomedical researcher. The PI?s immediate career goals are to acquire the knowledge in using supercomputers and the experimental skills of electrophysiology and microscopy necessary to develop a quantitative understanding of atrial excitation-contraction (E-C) coupling. The Pl?s long-term career goal is to lead a multidisciplinary team of physiologists, mathematicians, physicians, and computer programmers in developing a quantitative understanding of both normal and pathological E-C coupling in atrial cells. Mammalian ventricular cells have an extensive transverse(t)-tubular system that rapidly conducts the action potential from the cell surface to the interior triggering a near synchronous calcium (Ca) release from the sarcoplasmic reticulum (SR) and activation of myofibrils throughout the cell. Atrial cells lack an extensive t-tubular system. How Ca release from the SR far from the cell surface is triggered is unclear. The overall hypothesis is that in atrial cells, Ca entry during an action potential triggers regenerative Ca release from the SR at the cell surface and this regenerative Ca release (""""""""Ca wave"""""""") propagates as a wave radially to the center of the cell.
The Specific Aims are: (1) Test this hypothesis by correlating atrial single-cell contraction rate and magnitude with the Ca wave?s velocity and amplitude using video rate 2-dimensional confocal microscopy and fluorescent Ca indicators. (2) Develop a mathematical model of the atrial cell Ca control system and solve the model numerically using supercomputers. (3) Evaluate the model by comparing the model?s predictions with experimental measurements of Ca waves in voltage-clamped atrial cells using confocal microscopy. A quantitative model of the atrial Ca control system is necessary for understanding both normal E-C coupling and the origins of pathological spontaneous Ca waves, which recent data suggest can trigger atrial arrhythmias.
