Regulation of Liver by Nuclear Ca2+ Signaling

肝脏管理着广泛的代谢功能，这些功能是由相互关联的信号通路控制的。其中一个途径涉及肝细胞的胞质Ca2+信号，其调节胆汁分泌、葡萄糖代谢和细胞骨架组织等活动。该计划项目的目标是研究互补的Ca2+信号系统的机制和作用，在肝细胞的细胞核内。在目前的研究中发现，细胞核和细胞质中的游离Ca2+可以单独控制，基因转录、肝细胞生长和脂肪变性的发生是由细胞核Ca2+通过下游活化丝裂原活化蛋白激酶（MAPK）和MAPK磷酸酶-1 （MKP-1）途径调节的。在下一个奖励期内，我们将验证以下假设：生长因子通过位于核质网上的肌醇1,4,5-三磷酸受体（InsPSRs）释放核Ca2+来调节肝脏生长；核Ca2+信号的激活通过动态作用于阳性（MAPK）和阴性（MKP-1）调节信号通路来控制参与肝脏生长和再生的基因表达。这将通过以下项目进行测试：

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 bile secretion, glucose metabolism, and cytoskeletal organization. The 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 free Ca2+ in the nucleus and cytosol can be controlled separately, and that gene transcription, hepatocyte growth, and development of steatosis are regulated by nuclear Ca2+ through downstream activation of the mitogen-activated protein kinase (MAPK) and MAPK phosphatase-1 (MKP-1) pathways. During the next award period we will test the hypothesis that growth factors regulate liver growth by release of nuclear Ca2+ from inositol 1,4,5-trisphosphate receptors (InsPSRs) that reside on the nucleoplasmic reticulum, and that activation of nuclear Ca2+ signals controls gene expression involved in hepatic growth and regeneration by dynamically acting on both positive (MAPK) and negative (MKP-1) regulatory signaling pathways. This will be tested through the following projects: Project by Nathanson will determine whether and how receptor tyrosine kinases regulate growth of hepatocytes by inducing lnsP3-mediated Ca2+ signals within the nucleus. Project by Ehrlich will investigate whether and how MAPK and the MAPK phosphatase, MKP-1, differentially regulate the function and distribution of nuclear and cytosolic InsPSRs. Project by Bennett will investigate how local Ca2+ signals within the cytosol or nucleus control MKP-1 expression in order to modulate the magnitude and kinetics of gene activity required for liver growth and metabolism. 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+ provides a local conduit in the nucleus for the control of MAPK-mediated gene expression 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 associated metabolic syndromes such as non-alcoholic fatty liver disease (NAFLD).