(PQ6)Nuclear receptor mechanisms in circadian disruption induced hepatocarcinogenesis

(PQ6)昼夜节律紊乱诱导肝癌发生中的核受体机制

• 批准号: 10470137
• 负责人: LONING None FU
• 金额: $ 46.75万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470137
• 关键词: Ablation; Acids; Address; Affect; Agonist; Androstanols; Animal Model; Automobile Driving; Back; Bile Acid Biosynthesis Pathway; Bile Acids; Biological Markers; CAR receptor; CTNNB1 gene; Cancer Etiology; Cessation of life; Cholestasis; Chronic; Chronotherapy; Circadian Dysregulation; Circadian Rhythms; Cirrhosis; Coupled; Detection; Development; Drug Targeting; Early Diagnosis; Endocrine; Epidemic; Failure; Fatty acid glycerol esters; Fibrosis; Gene Expression; Gene Mutation; Genes; Genetic; Genome; Hawaii; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocarcinogenesis; Homeostasis; Hour; Human; Impairment; Incidence; Individual; Institutes; Intrahepatic Cholestasis; Jet Lag Syndrome; Knock-out; Length; Lesion; Light; Link; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Metabolic; Metabolic Control; Metabolic syndrome; Molecular; Mutation; Nodule; Nuclear; Nuclear Receptors; Obesity; Obesity Epidemic; Oncogene Deregulation; Oncogenic; Organ; Pathologic; Pathology; Pathway interactions; Peripheral; Population; Prevalence; Prevention; Prevention approach; Prevention strategy; Primary carcinoma of the liver cells; Resistance; Risk; Risk Factors; Role; Schedule; Security; Serum; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tumor Promoters; Western World; Wild Type Mouse; Xenobiotic Metabolism; Xenobiotics; biomarker signature; carcinogenesis; circadian; clinically relevant; gene network; genetic signature; genome-wide; improved; liver metabolism; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; predictive test; premalignant; prevent; rare cancer; receptor; response; shift work; transcriptome sequencing; tumor

Project Summary This application addresses NCI PQ6 on how circadian processes affect tumor development by studying the role of circadian dysfunction of nuclear receptor pathways in non-alcoholic fatty liver disease (NAFLD)- induced hepatocellular carcinoma (HCC). HCC, previously considered a rare cancer in the Western world, has increased 3-fold in incidence since the 1980s, and is currently the fastest rising cause of cancer-related death in the U.S, due to an increase in incidence in combination of lack of understanding of its mechanism. The increased HCC risk is coupled with the prevalence of obesity-related NAFLD, which has recently become the leading risk factor for HCC. However, no efficient approaches for prevention, early diagnosis, and treatment of NAFLD-induced HCCs are currently available. The increased risk of NAFLD-related HCC is coupled with population-wide chronic circadian disruption, a common risk factor of obesity, NAFLD, and cancer in humans. We have recently established a jet-lagged mouse model following a human nightshift schedule. We found that chronic jet-lag induces metabolic syndrome, NAFLD, and HCC in wild-type mice following a pathophysiological pathway strikingly similar to that observed in obese humans, with NAFLD progressing to nonalcoholic steatohepatitis (NASH) and fibrosis prior to HCC detection. We identified intrahepatic cholestasis as the key pathophysiological mechanism promoting NAFLD-induced HCC, and demonstrated that circadian dysregulation of nuclear receptor FXR and CAR pathways is an essential oncogenic mechanism that drives cholestasis and toxic bile acid signaling to promote the progression from NAFLD to NASH, fibrosis, and eventually HCC. In this application, we propose 3 aims. 1) Define the circadian profiles of FXR and CAR controlled hepatic gene networks and jet-lag induced deregulation signatures of these gene networks. 2) Define the role of Ctnnb1 and Tp53 and other oncogenic mutations in the progression from jet-lag induced liver premalignant lesions to HCC and the circadian profiles of gene signatures as well as serum biomarkers associated with hepatocarcinogenesis. 3) Test the predicted abilities of FXR agonist obeticholic acid (OCA) and CAR inverse agonist androstanol (ANDR) to prevent jet-lag induced cholestasis and HCC. These studies will significantly improve our understanding of the role of circadian dysfunction in spontaneous carcinogenesis in general, and NFALD-induced hepatocarcinogenesis in particular. They will also illuminate new and exciting avenues to develop novel chronotherapy strategies for prevention and treatment of NAFLD-induced HCC in humans.

项目摘要 这个应用程序解决了NCI PQ6关于昼夜节律过程如何影响肿瘤发展的研究 核受体昼夜节律失调在非酒精性脂肪性肝病中的作用 诱导性肝细胞癌。 此前在西方世界被认为是一种罕见癌症的肝癌，自那以来发病率增加了3倍 20世纪80年代，目前是美国癌症相关死亡人数上升最快的原因，原因是 发病结合缺乏对其发病机制的认识。增加的肝细胞癌风险与 随着肥胖相关NAFLD的流行，NAFLD最近已成为肝细胞癌的首要危险因素。 然而，没有有效的方法来预防、早期诊断和治疗非酒精性脂肪肝所致的肝细胞癌 目前都是可用的。与非酒精性脂肪肝相关的肝癌风险增加与整个人群的慢性疾病有关 昼夜节律紊乱是人类肥胖、非酒精性脂肪肝和癌症的常见危险因素。我们最近做了 按照人类的夜班时间表建立了一种时差反应的小鼠模型。我们发现慢性时差反应 通过病理生理途径诱导野生型小鼠代谢综合征、非酒精性脂肪肝和肝癌 与在肥胖者身上观察到的惊人相似，NAFLD进展为非酒精性 脂肪性肝炎(NASH)和肝细胞癌检测前的纤维化。我们将肝内胆汁淤积症确定为 促进NAFLD诱导的肝癌的关键病理生理机制，并证明昼夜节律 核受体FXR和CAR通路的失调是一种重要的致癌机制 推动胆汁淤积和毒性胆汁酸信号转导，促进NAFLD向NASH、纤维化、 最后是肝细胞癌。 在本申请中，我们提出了三个目标。1)确定FXR和CAR控制的肝脏的昼夜节律 基因网络和时差导致这些基因网络的去调控特征。2)定义 CTNNB1和TP53等癌基因突变与时差致肝癌前病变进展的关系 肝细胞癌的病变和基因特征的昼夜变化以及与之相关的血清生物标志物 肝癌的发生。3)检验FXR激动剂乙酰胆酸(OCA)和CAR的预测能力 反向激动剂雄烷醇(ANDR)预防时差引起的胆汁淤积和肝细胞癌。 这些研究将显著提高我们对昼夜节律紊乱在 一般是自发致癌，特别是NFALD诱发的肝癌。他们会 还阐明了新的和令人兴奋的途径，以开发新的时间疗法战略，以预防和 非酒精性脂肪肝诱发人肝细胞癌的治疗。