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。其中一个途径涉及肝细胞的胞质Ca2+信号，其调节转运和胆汁分泌、细胞骨架组织和凋亡等活动。本项目的持续目标是研究肝细胞核内互补Ca2+信号系统的机制和作用。本研究发现，生长因子通过先前未被识别的肝细胞核内Ca2+信号通路调节细胞增殖，0- glcnac酰化修饰蛋白是lnsP3受体/Ca2+释放通道分子调控的潜在新调控机制，核特异性MAPK磷酸酶MKP-1参与脂质代谢调控和肝脂肪变性的发生。在下一个奖励期间，我们将测试肝脏生长和代谢之间的平衡是由肝细胞核中的Ca2+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Ca2+信号以调节肝细胞生长，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细胞质中lnsP3受体0- glcn酰化的影响，以及这如何影响肝细胞中的Ca2+信号。项目3将测试内质网和细胞核中的应激是否会损害核Ca2+信号，并通过破坏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核Ca2+如何调节肝脏生长和代谢平衡的全面研究。这些研究的结果将对肝脏生长调节受损的肝病的治疗具有广泛的临床意义，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）。

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).