Sympathetic circadian dysfunction in obesity-related hepatocarcinogenesis

项目摘要 这个RO1应用程序通过研究昼夜节律紊乱在NCI PQ6中的作用直接解决了NCI PQ6 交感神经系统在肝癌发生中的作用回溯性临床研究强烈表明 交感神经功能障碍是人类癌症的关键致病因素，阻滞剂是潜在的抗癌药物 探员们。然而，交感神经功能障碍在肿瘤发生中的作用和阻滞剂的作用机制 抗癌效应是人们认识上的重大鸿沟。我们将定义昼夜节律影响的分子基础 交感神经系统(SNS)在自发性肝癌发生中的调节失调及检测 阻滞剂预防非酒精性脂肪性肝病诱导的肝细胞癌的能力 (肝细胞癌)。 自20世纪80年代以来，肝癌的发病率增加了3倍，目前它是 美国与癌症相关的死亡。肝癌发病率的增加与肥胖症的流行相结合， 与肥胖相关的非酒精性脂肪肝和慢性昼夜节律紊乱。非酒精性脂肪肝现在正在成为肝细胞癌的主要驱动力 在21世纪。然而，没有有效的方法来预防、早期诊断和治疗NAFLD- 诱导的肝细胞癌是可用的。我们发现慢性昼夜节律失调会导致肥胖相关的代谢 正常饲喂野生型小鼠的综合征、NAFLD和肝癌遵循显著的病理生理途径 与在肥胖人群中观察到的情况类似。我们确定肝内胆汁淤积症是关键的近端 促进NAFLD进展为非酒精性脂肪性肝炎的病理生理机制 (NASH)，纤维化，最终导致肝癌。我们证明了的昼夜节律紊乱- 肾上腺素能受体(Adr)介导的交感信号是驱动 核受体功能障碍、胆汁淤积和致癌激活促进肝细胞癌的发生。 我们提出3个主要目标来研究交感神经功能障碍在肝癌发生中的作用：1) 表征与ADR介导的SNs昼夜节律障碍相关的肝脏基因失控特征 由ChIPseq和RNAseq提供。2)明确ADR昼夜节律紊乱所致的血清和肝胆汁酸谱， 肝脏病理、肝细胞癌风险和癌前基因信号驱动肝细胞癌的发生。3)定义的角色- 阻滞剂心得安预防非酒精性脂肪肝相关肝细胞癌的昼夜节律紊乱。 我们的研究将不仅确定交感昼夜节律紊乱在NFALD诱导的致癌中的作用 激活和肝癌的发生，但也为设计阻滞剂提供了前所未有的机会- 定向的个性化和互补性的抗肝癌时序治疗策略。

Project Summary This RO1 application directly addresses NCI PQ6 by investigating the role of circadian dysfunction of the sympathetic nervous system (SNS) in hepatocarcinogenesis. Retrospective clinical studies strongly suggest that sympathetic dysfunction is a key etiologic factor in human cancers, and that -blockers are potential anticancer agents. However, the role of sympathetic dysfunction in tumorigenesis and the mechanisms of -blocker-directed anticancer effects are significant knowledge gaps. We will define the molecular basis for the impact of circadian dysregulation of the sympathetic nervous system (SNS) on spontaneous hepatocarcinogenesis and test the ability of -blockers to prevent non-alcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma (HCC). The incidence of HCC has increased >3-fold since the 1980s and it is currently the fastest rising cause of cancer-related death in the U.S. The increase in HCC incidence is coupled with the prevalence of obesity, obesity-related NAFLD, and chronic circadian disruption. NAFLD is now emerging as the leading driver of HCC in the 21st century. However, no efficient approaches for prevention, early diagnosis, and treatment of NAFLD- induced HCC are available. We discovered that chronic circadian dysfunction induces obesity-related metabolic syndrome, NAFLD, and HCC in normal chow fed wild-type mice following a pathophysiological pathway strikingly similar to that observed in obese humans. We identified intrahepatic cholestasis as the key proximal pathophysiological mechanism that stimulates the progression from NAFLD to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually hepatocarcinogenesis. We demonstrated that circadian dysfunction of - adrenergic receptor (ADR)-mediated sympathetic signaling is an essential molecular mechanism that drives nuclear receptor dysfunction, cholestasis and oncogenic activation to promote HCC. We propose 3 broad aims to study the role of sympathetic dysfunction in hepatocarcinogenesis: 1) Characterize hepatic gene deregulation signatures associated with ADR-mediated SNS circadian dysfunction by ChIPseq and RNAseq. 2) Define ADR circadian dysfunction induced serum and hepatic bile acid profiles, liver pathologies, HCC risk, and the premalignant gene signature driving HCC initiation. 3) Define the role of - blocker propranolol in prevention of circadian dysfunction-induced NAFLD-associated HCC. Our studies will not only define the role of sympathetic circadian dysfunction in NFALD-induced oncogenic activation and hepatocarcinogenesis, but also provide an unprecedented opportunity to design -blocker- directed personalized and complementary strategies for anti-HCC chronotherapy.