Alcohol, nuclear receptor signaling, and circadian clocks

描述(申请人提供)：酒精性肝病(ALD)的范围从脂肪变性到肝硬变，是慢性肝病的主要原因。昼夜节律系统包括一个复杂的反馈网络，涉及中枢神经系统和周围组织之间的相互作用。昼夜节律紊乱是ALD发生的危险因素。然而，生物钟和ALD之间的联系在很大程度上仍未被探索。此外，最先进的分析工具，如转录组学(RNA-seq)和代谢组学(GC/MS)，还没有被很好地用于ALD的研究。核受体是分子时钟机制和代谢性疾病之间的关键中介。我的实验室在小异源二聚体(SHP)的体内功能方面取得了开创性的发现，最近还发现SHP在整合肝脏时钟和代谢网络中发挥着关键作用。这项应用的目的是确定肝脏和/或中枢时钟和时钟控制基因在酒精性脂肪性肝病中的作用，并与肝脏代谢产物的节律性中断相关。这一应用的假设是，酒精诱导的脂肪肝是由肝脏/中枢时钟基因通过SHP依赖和SHP非依赖机制介导的。目的1：建立完整的肝脏昼夜节律网络，发现酒精依赖和独立调节的振荡代谢物；目标2：建立酒精依赖和独立调节的中枢昼夜节律网络。我们将使用NIAAA的高斌博士开发的一个简单的酒精暴饮症模型，以及我们独特的SHP-/-小鼠在不同环境线索(光/暗周期)下的模型。下一代RNA测序将分析酗酒调控基因在肝脏中的节律表达，而血浆和肝脏代谢物的日变化将通过GC/MS代谢组学分析来确定。预期的结果是建立受酗酒影响的整个肝脏转录组和代谢组。这项研究将提供必要的基础知识，以确定肝脏/中枢生物钟与酒精性脂肪肝之间的关键联系。因此，拟议的创新研究有望使ALD研究取得实质性进展，使该项目具有很高的临床意义，并与NIAAA的使命高度相关。

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) ranges from steatosis to cirrhosis and is a major cause of chronic liver diseases. The circadian system comprises a complex feedback network that involves interactions between the central nervous system and peripheral tissues. Disturbance of circadian rhythmicity is a risk factor for the development of ALD. However, the association between circadian clocks and ALD remains largely unexplored. In addition, the most advanced analytical tools, such as transcriptomics (RNA-seq) and metabolomics (GC/MS), have not been well utilized to study ALD. Nuclear receptors are key mediators between the molecular clock machinery and metabolic diseases. My laboratory has made pioneering discoveries regarding the in vivo function of small heterodimer partner (SHP) and has recently uncovered a critical role for SHP in the integration of the liver clock and metabolic network. The objective of this application is to determine the role of the liver and/or central clock and clock- controlled genes in alcohol-induced fatty liver disease associated with disruption of rhythmicity of hepatic metabolites. The hypothesis of this application is that alcoho induced fatty liver is mediated by liver/central clock genes via SHP-dependent and SHP-independent mechanisms. Aim #1: To build comprehensive hepatic circadian networks and discover oscillatory metabolites regulated by ethanol- binge in a SHP dependent and independent fashion; and Aim #2: To establish central circadian networks regulated by ethanol-binge in a SHP dependent and independent fashion. We will use a simple ethanol- binge model developed by Dr. Bin Gao at NIAAA and our unique SHP-/- mice under different environmental cues (light/dark cycles). The rhythmic expression of genes in the liver regulated by ethanol-binge will be analyzed by next generation RNA-sequencing, while the diurnal variations of plasma and liver metabolites will be determined by GC/MS metabolomics analysis. The anticipated result is establishing the entire liver transcriptome and metabolome affected by alcohol-binge. The study will provide fundamental knowledge required to establish a crucial link between the liver/central clock and alcoholic fatty liver. Therefore, the innovative research proposed is expected to enable substantial advances in ALD research, making this project of high clinical significance and of high relevance to the mission of NIAAA.