Regulation of Liver by Nuclear Ca2+ Signaling

肝脏管理广泛的代谢功能，这些功能由相互关联的信号控制 途径。其中一种途径涉及肝细胞中的胞质Ca 2+信号传导，其调节活性 如胆汁分泌、葡萄糖代谢和细胞骨架组织。本项目的目标 目的是研究细胞核内补充性Ca 2+信号系统的机制和作用， 肝细胞在目前的奖项，它被发现，游离Ca 2+在细胞核和胞质溶胶中，可以是 单独控制，基因转录，肝细胞生长和脂肪变性的发展， 通过丝裂原活化蛋白激酶（MAPK）的下游激活受细胞核Ca 2+调节 和MAPK磷酸酶-1（MKP-1）途径。在下一个奖项期间，我们将测试假设， 生长因子通过从肌醇1，4，5-三磷酸受体释放细胞核Ca 2+调节肝脏生长 细胞核内Ca 2+信号的激活控制着细胞核内钙离子的释放， 通过动态作用于两种阳性信号（MAPK）参与肝生长和再生的基因表达 和负性（MKP-1）调节信号通路。这将通过以下项目进行检验： Nathanson的项目将确定受体酪氨酸激酶是否以及如何调节肝细胞的生长， 在细胞核内诱导InsP 3介导的Ca 2+信号。 埃利希的项目将研究MAPK和MAPK磷酸酶MKP-1是否以及如何差异调节 核和胞浆InsPSR的功能和分布。 班尼特的项目将研究细胞质或细胞核内的局部Ca 2+信号如何控制MKP-1的表达， 以调节肝脏生长和代谢所需的基因活性的大小和动力学。 为了帮助实施这些项目，将建立细胞和分子生物学，细胞 成像和给药。这些项目将共同提供一个全面的调查， 细胞核内Ca ~（2+）为MAPK介导的基因表达提供了一个局部通道， 肝脏这些研究的结果将对肝脏疾病的治疗具有广泛的临床意义 其中肝生长调节受损，包括肝硬化和肝细胞癌，以及 作为相关的代谢综合征，如非酒精性脂肪性肝病（NAFLD）。

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).