MECHANISMS OF IONIC SIGNALING BY HEPATIC GROWTH FACTORS

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The applicant is fully committed to a career in laboratory-based investigation and has designed this proposal to build upon and to broaden the skills and scientific interests developed during his fellowship training. The studies outlined in this proposal will enable the applicant to apply this background to questions that are fundamental to understanding aspects of hormonal signal transduction and regulation of cellular proliferation. The aim of the proposed project is to investigate the hepatocellular mechanisms of ionic signaling in response to growth factors, specifically to identify growth factor activated ion entry pathways and the mechanisms by which this activation occurs, and also to identify the role of altered ion flux in modulating proto-oncogene expression, an early downstream growth factor response. The experimental design employs several complementary approaches to address the overall goals. These approaches include real-time measurement of growth factor induced perturbations in cytosolic cation concentrations and electrophysiologic detection of ion currents responsible for this perturbation, definition of the role of ionic signaling in modulation of proto-oncogene expression, and expression cloning of growth factor activated ion channels/transporters in Xenopus oocytes.