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，其调节诸如胆汁分泌、葡萄糖代谢和细胞骨架组织的活动。本计划项目的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，发现细胞核和胞质溶胶中的游离Ca 2+可以单独控制，并且基因转录、肝细胞生长和脂肪变性的发展由核Ca 2+通过促分裂原活化蛋白激酶（MAPK）和MAPK磷酸酶-1（MKP-1）途径的下游活化来调节。在下一个奖项期间，我们将测试的假设，即生长因子调节肝细胞生长的释放核钙从肌醇1，4，5-三磷酸受体（InsPSR），驻留在核质网上，和核钙信号的激活控制基因表达参与肝细胞生长和再生，通过动态作用于积极的（MAPK）和消极的（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通过诱导细胞核内InsP 3介导的Ca 2+信号来调节肝细胞的生长。 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质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Ca 2+提供了一个本地管道，在细胞核中的MAPK介导的基因表达的控制， 肝脏这些研究的结果将对肝脏生长调节受损的肝脏疾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).