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: 8598857
• 负责人: WENDONG HUANG
• 金额: $ 33.41万
• 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/8598857
• 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.

性状（申请人提供）：法尼醇X受体（FXR，NR 1H 4）属于核受体超家族，是肝脏代谢（包括胆汁酸（BA）、脂质和葡萄糖代谢）中的关键代谢调节因子。我们最近证明，FXR-/-小鼠随着年龄的增长自发地发展肝肿瘤，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）中的新作用。HCC仍然是全球癌症死亡的主要原因，并且HCC在发达国家（包括美国）的发病率正在增加。虽然有几种HCC动物模型，但FXR-/-小鼠提供了一种独特的病理相关模型来研究HCC发展机制，特别是肝脏代谢与肝癌发生之间的病因学联系。FXR-/-小鼠肝癌的发生发展与人类肝癌的病理过程相似，因此，更好地了解FXR在肝癌中的作用将有助于我们发现新的靶点，为肝癌的预防和治疗提供新的方法。基于我们以前的工作和更多的初步数据伴随着这一建议，我们假设FXR是一种新的肝脏保护和肝癌抑制。具体而言，FXR调节超氧化物歧化酶（EC-SOD，SOD 3）和其他抗氧化应激基因的表达，这些基因抑制活性氧（ROS）的有害作用，并防止肝脏中JNK 1的长期激活。FXR还直接调节抗凋亡途径中基因的表达，并且FXR的功能障碍导致细胞死亡和肝损伤增强，从而促进HCC的发展。我们在这个建议中提出了两个具体目标。在第一个目标中，我们将定义FXR在ROS代谢和JNK 1激活中的作用及其与HCC发展的联系。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HCC中的作用，并为人类肝癌的发生提供见解。拟议的工作是创新的，因为拟议的研究将定义肝脏代谢和HCC之间的新联系。成功完成拟议的研究将导致开发新的方法来预防和治疗肝癌。