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内的胞浆钙信号，它调节诸如运输和胆汁分泌、细胞骨架组织和细胞凋亡等活动。该计划项目的持续目标是研究肝细胞核内互补的钙信号系统的机制和作用。在本次研究中，发现生长因子通过肝细胞核内未知的钙信号通路调节细胞增殖，0-GlcN酰化修饰的蛋白质是调节lnsP3受体/钙释放通道分子的潜在新的调控机制，核特异性MAPK磷酸酶MKP-1参与调节脂质代谢和肝脏脂肪变性的发生。在下一个获奖期，我们将检验这样一种假设，即肝脏的生长和代谢之间的平衡是由肝细胞核中的钙信号调节的。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钙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胞浆中lnsP3受体0-GlcN酰化的影响，以及这如何影响肝细胞中的钙信号。项目3将测试内质网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靶标来破坏核钙信号转导和促进肝脏脂肪变性。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关于核钙如何调节肝脏生长和新陈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，包括肝硬变和肝细胞癌，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).