A tight coupling between the electrical cell activity and intracellular calcium (Ca2+) dynamic underlies the regulation of cardiac muscle cell function. Various alterations in the proteins and pathways involved in these coupled processes are now recognized to be the primary mechanisms of cardiac dysfunction in a diverse range of common pathologies including 1,4,5- trisphosphae(IP3)-mediated arrhythmias and hypertrophy. As more experimental detail on the biochemistry and biophysics of these complex processes and their interactions accumulates, the intuitive interpretation of the new findings becomes increasingly impractical. The goal of the proposed research is to develop new computational tool for modeling Ca2+ and IP3 signaling in rabbit ventricular myocytes. The new tool will be used to test hypotheses regarding excitation- contraction and excitation-transcription coupling under physiological and certain pathological conditions (arrhythmias, hypertrophy).
The specific aims are: (1) Test how the cytoplasmic Ca2+ regulates nuclear Ca2+ under control conditions;(2) Test how localized IP3-mediated increases in nuclear Ca2+ can occur during normal excitation-contraction coupling;(3) Test how prolonged stimulation with IP3 modulates the intracellular Ca2+ dynamics in rabbits. The new computational tool and data resulting from this project will be implemented in highly portable, modular and readily used software and data formats that will be maintained by the National Biomedical Computational Resource at UCSD (://www.nbcr.net/).
The applicant proposes to develop new biophysical model in rabbit ventricular myocytes that connects cell excitability with Ca2+ and IP3 signaling in the cytosol and nucleus. The computational tool will be implemented in highly portable, modular and readily used software and data formats that will be maintained by the National Biomedical Computational Resource at UCSD. To validate the model the applicant will use published and new experimental data on the activation and regulation of excitation-contraction and excitation-transcription coupling under physiological conditions and during prolonged stimulation of the cell with neurohormonal agonist endothelin-1.
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