Regulation of Liver by Nuclear Ca2+ Signaling

描述（由申请人提供）：肝脏管理广泛的代谢功能，这些功能由相互关联的信号通路控制。其中一种途径涉及肝细胞中的胞质Ca 2+信号传导，其调节诸如转运和胆汁分泌、细胞骨架组织和细胞凋亡的活动。该计划项目的持续目标是研究肝细胞核内互补Ca 2+信号系统的机制和作用。在当前的奖项期间，发现生长因子通过肝细胞核中先前未被识别的Ca 2+信号传导途径来调节细胞增殖，通过0-GlcNAc酰化的蛋白质修饰是用于InsP 3受体/Ca 2+释放通道的分子调节的潜在新控制机制，并且核特异性MAPK磷酸酶MKP-1参与脂质代谢的调节和肝脂肪变性的发展。在下一个奖项期间，我们将测试肝脏中生长和代谢之间的平衡由肝细胞核中的Ca 2+信号调节的假设。这将通过三个项目进行测试。项目1将确定受体酪氨酸激酶如何控制细胞核中的Ca 2+信号传导以调节肝细胞生长，以及脂肪肝如何损害这些途径。项目2将研究脂肪酸和葡萄糖对细胞核和胞质溶胶中InsP 3受体的0-GlcNAc化的影响，以及这如何影响肝细胞中的Ca 2+信号传导。项目3将测试ER和细胞核中的应激是否通过破坏MKP-1介导的控制肝脏脂肪生成的MAPK靶点的调节来损害细胞核Ca 2+信号传导并促进肝脏脂肪变性。为了帮助实施这些项目，将建立细胞和分子生物学、细胞成像和管理的核心设施。这些项目将共同提供一个全面的调查如何核钙2+调节生长和代谢之间的平衡在肝脏。这些研究的结果将对治疗肝脏生长调节受损的肝脏疾病（包括肝硬化和肝细胞癌）以及代谢综合征（如非酒精性脂肪性肝病（NAFLD））具有广泛的临床意义。

DESCRIPTION (provided by applicant): The liver manages a wide range of metabolic functions, which are controlled by interrelated signaling pathways. One such pathway involves cytosolic Ca2+ signaling in hepatocytes, which regulates activities such as transport and bile secretion, cytoskeletal organization, and apoptosis. The ongoing goal of this Program Project is to examine the mechanisms and effects of a complementary Ca2+ signaling system, within the nucleus of hepatocytes. During the current award it was found that growth factors act through a previously unrecognized Ca2+ signaling pathway in the nucleus of hepatocytes to regulate cell proliferation, that protein modification by 0-GlcNAcylation is a potential new control mechanism for the molecular regulation of the lnsP3 receptor/Ca2+ release channel, and that the nuclear-specific MAPK phosphatase MKP-1 is involved in the regulation of lipid metabolism and development of hepatic steatosis. During the next award period we will test the hypothesis that the balance between growth and metabolism in the liver is regulated by Ca2+ signals in the nucleus of hepatocytes. This will be tested through three projects. Project 1 will determine how receptor tyrosine kinases control Ca2+ signaling in the nucleus to regulate hepatocyte growth, and how fatty liver impairs these pathways. Project 2 will investigate the effects of fatty acids and glucose on 0-GlcNAcylation of the lnsP3 receptor in the nucleus and cytosol, and how this affects Ca2+ signaling in hepatocytes. Project 3 will test whether stress in the ER and nucleus impairs nuclear Ca2+ signaling and promotes hepatic steatosis by disrupting MKP-1-mediated regulation of MAPK targets that control hepatic lipogenesis. To help carry out these projects, core facilities will be established for cell and molecular biology, cell imaging, and administration. These projects will collectively provide a comprehensive investigation of how nuclear Ca2+ regulates the balance between growth and metabolism in the liver. The results of these studies will have broad clinical implications for the treatment of liver diseases in which regulation of hepatic growth is impaired, including cirrhosis and hepatocellular carcinoma, as well as metabolic syndromes such as non-alcoholic fatty liver disease (NAFLD).