The liver performs certain unique physiologic functions, and these are regulated in part by cytosolic Ca2+. The liver also is unique because it has the capacity to regenerate, even after most of the organ has been removed. However, chronic hepatocellular damage can lead to cirrhosis, and dysregulation of regeneration can lead to hepatocellular carcinoma, the most common malignancy in the world. Like other functions of the liver, growth of hepatocytes is regulated in part by Ca2+, but it is unclear whether hepatocyte growth is controlled by Ca2+ in the nucleus or cytosol. Since changes in both nuclear and cytosolic Ca2+ are mediated by inositol 1,4,5-trisphosphate (InsP3), the hypothesis of this project is that Ca2+ in the nucleoplasm of hepatocytes is regulated by distinct nuclear InsP3 receptors, and that nuclear Ca2+ regulates cell growth. This hypothesis will be tested through the following specific aims: 1. The location of InsP3-dependent Ca2+ stores in the nucleus will be identified. Hepatocytes and liver cell lines will be examined by confocal microscopy using fluorescent dyes of organelles and isoform-specific InsP3 receptor antibodies. 2. The conditions under which InsP3 releases Ca2+ in the nucleus, cytosol, or both will be determined. Two-photon flash photolysis of caged InsP3 and caged Ca2+ will be used to selectively examine Ca2+ release in the nucleus and in the cytosol. 3. The effects of nuclear vs. cytosolic Ca2+ signals on cell growth will be examined. Hepatocyte cell lines that express an endogenous Ca2+ chelator that is localized to either the nucleus or cytosol will be constructed to investigate this. Together, these studies should reveal how nuclear Ca2+ release is controlled in intact cells, and determine the distinct role this may play in regulating the growth and function of hepatocytes.
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