INVESTIGATION OF THE ROLES OF NUCLEAR RECEPTOR FXR IN HEPATOCELLULAR

核受体 FXR 在肝细胞中的作用研究

• 批准号: 8403839
• 负责人: WENDONG HUANG
• 金额: $ 32.38万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-25 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403839
• 关键词: Animal Model; Antioxidants; Apoptosis; Apoptotic; BCL2 gene; Bile Acids; Cancer Etiology; Cell Death; Cessation of life; Chemicals; Data; Developed Countries; Development; Diethylnitrosamine; Functional disorder; Gene Expression; Gene Targeting; Genes; Goals; Hepatic; Hepatocarcinogenesis; Hepatocyte; Human; Incidence; Inflammation; Investigation; Knockout Mice; Lead; Link; Liver; Liver neoplasms; MAPK8 gene; Malignant Neoplasms; Mediating; Medical; Metabolic; Metabolism; Modeling; Mus; Natural regeneration; Nuclear Receptors; Oxidative Stress; Pathway interactions; Play; Positioning Attribute; Prevention; Prevention therapy; Primary carcinoma of the liver cells; Publications; Reactive Oxygen Species; Receptor Activation; Research; Role; Stimulus; Superoxide Dismutase; Testing; United States; Work; aged; base; effective therapy; glucose metabolism; glutathione peroxidase; innovation; insight; lipid metabolism; liver injury; liver metabolism; novel; novel strategies; prevent; public health relevance; receptor; tumor metabolism

DESCRIPTION (provided by applicant): Farnesoid X Receptor (FXR, NR1H4) belongs to nuclear receptor superfamily and is a key metabolic regulator in liver metabolism, including bile acid (BA), lipid and glucose metabolism. We recently demonstrated that FXR-/- mice spontaneously developed liver tumors as they aged and the mice displayed prominent liver injury, inflammation and irregular regeneration. These results suggest a novel role of FXR in suppressing hepatocellular carcinoma (HCC). HCC remains a major cause of cancer death worldwide, and the incidence of HCC in developed countries, including the United States, is increasing. Although there are several animal models of HCC, FXR-/- mice provide a unique pathologically relevant model to study the mechanism of HCC development, especially the etiological connection between liver metabolism and hepatocarcinogenesis. The development of HCC in FXR-/- mice mimics the pathological progression of human HCC, therefore, better understanding the roles of FXR in HCC will help us to identify new targets and provide novel approaches for HCC prevention and therapy. Based on our previous work and more preliminary data accompanying this proposal, we hypothesize that FXR is a novel liver protector and HCC suppressor. Specifically, FXR regulates the expression of a superoxide dismutase (EC-SOD, SOD3) and other anti-oxidative stress genes that suppress the deleterious effect of reactive oxygen species (ROS) and prevents prolonged JNK1 activation in liver. FXR also directly modulates the expression of genes in anti-apoptosis pathways, and that dysfunction of FXR results in enhanced cell death and liver injury, thereby promoting the HCC development. We propose two Specific Aims in this proposal. In the first Aim, we will define the roles of FXR in ROS metabolism and JNK1 activation and their link to HCC development. In the second Aim, we will determine the roles of FXR in regulating the expression of anti-apoptotic genes. These experimental approaches will help us better understand the roles of FXR in HCC and provide insight into the human hepatocarcinogenesis. The proposed work is innovative as the proposed studies will define a novel link between liver metabolism and HCC. Successful completion of the proposed studies will lead to the development of novel approaches for the prevention and treatment of HCC.

描述(申请人提供)：法尼醇X受体(FXR，NR1H4)属于核受体超家族，是肝脏代谢的关键代谢调节因子，包括胆汁酸(BA)、脂肪和葡萄糖代谢。我们最近证实，FXR-/-小鼠随着年龄的增长自发地发展为肝肿瘤，并且小鼠表现出明显的肝损伤、炎症和不规则的再生。这些结果表明，FXR在抑制肝细胞癌(HCC)方面具有新的作用。肝癌仍然是全球癌症死亡的主要原因，在包括美国在内的发达国家，肝癌的发病率正在上升。尽管有多种肝细胞癌的动物模型，但FXR-/-小鼠为研究肝细胞癌的发生机制，尤其是肝代谢与肝癌发生之间的病因学联系提供了独特的病理模型。在FXR-/-小鼠体内发生的肝细胞癌与人类肝细胞癌的病理过程相似，因此，更好地了解FXR在肝细胞癌中的作用有助于我们发现新的靶点，为肝细胞癌的预防和治疗提供新的途径。基于我们以前的工作和伴随这项提议的更多初步数据，我们假设FXR是一种新的肝脏保护剂和肝细胞癌抑制因子。具体地说，FXR调节超氧化物歧化酶(EC-SOD，SOD3)和其他抗氧化应激基因的表达，这些基因可以抑制活性氧物种(ROS)的有害影响，并防止肝脏中JNK1的长期激活。FXR还直接调控抗细胞凋亡途径中的基因表达，FXR功能障碍导致细胞死亡和肝损伤加重，从而促进肝癌的发生发展。我们在这项提案中提出了两个具体目标。在第一个目标中，我们将确定FXR在ROS代谢和JNK1激活中的作用及其与肝癌发生的联系。在第二个目标中，我们将确定FXR在调节抗凋亡基因表达中的作用。这些实验方法将有助于我们更好地了解FXR在肝癌中的作用，并为人类肝癌的发生提供洞察力。这项拟议的工作是创新的，因为拟议的研究将定义肝脏代谢和肝细胞癌之间的新联系。拟议研究的成功完成将导致开发预防和治疗肝细胞癌的新方法。