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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-5 (J2))
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Serrano, Jose
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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