Ca2+ plays an important role in the liver. In the cytosol, it regulates activities such as bile secretion, glucose metabolism and cytoskeletal organization. We hypothesize that Ca2+ in the neoplasm instead regulates processes such as hepatic growth and regeneration and gene transcription. The mechanism by which nucleoplasmic Ca2+ is regulated thus is of great potential importance. It has been suggested that nuclear Ca2+ passively follows cytosolic Ca2+, but our preliminary data instead suggest that there is nuclear machinery that allows nucleoplasmic Ca2+ to be controlled independent of the Ca2+ concentration in the cytosol. Such machinery would in turn allow independent regulation of Ca2+- mediated events in the nucleus. Since the inositol 1,4,5,-triphosphate (InsP3) receptor regulates Ca2+ signaling in hepatocytes, our hypothesis will be tested by systematically defining the mechanisms and effects of nuclear Ca2+ signaling in liver through the following projects: Project A The organization of nuclear Ca2+ stores and the factors that regulate release of Ca2+ from these stores will be determined in intact hepatocytes and in liver cell lines. Project B The function and regulation of both native and cloned nuclear InsP3 receptors of hepatocytes will be characterized at the single channel level. Project C The role of the mitogen-activated protein kinase (MAPK) phosphatase-1 (MAPK-1) in controlling MAPK-mediated liver-specific gene transcription events in response to nuclear Ca2+ signals will be examined. Project D The significance of nuclear Ca2+ signals for gene transcription in liver will be examined by determining how genes integral to liver- specific functions are regulated by Ca2+ and by Ca2+-mobilizing bile acids. To help carry out these projects, core facilities will be established for cell and molecular biology, cell imaging, and administration.
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