Alcohol, nuclear receptor signaling, and circadian clocks

描述（由申请人提供）：酒精性肝病（ALD）范围从脂肪变性到肝硬化，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外周组织之间的相互作用。昼夜节律紊乱是ALD发生的危险因素之一。然而，生物钟和ALD之间的关系在很大程度上仍未被探索。此外，转录组学（RNA-seq）和代谢组学（GC/MS）等最先进的分析工具尚未很好地用于研究ALD。核受体是分子钟机制与代谢性疾病之间的关键介质。我的实验室在小异二聚体伴侣（SHP）的体内功能方面取得了开创性的发现，最近发现了SHP在肝脏时钟和代谢网络整合中的关键作用。本应用程序的目的是确定肝脏和/或中央时钟和时钟控制基因在酒精诱导的脂肪肝疾病中与肝脏代谢物节律性破坏相关的作用。本应用的假设是，酒精诱导的脂肪肝是由肝/中枢时钟基因通过shp依赖性和非shp依赖性机制介导的。目的1：建立全面的肝脏昼夜节律网络，发现由乙醇暴饮以依赖和独立的方式调节的振荡代谢物；目标2：建立由酒精暴饮以SHP依赖和独立的方式调节的中央昼夜节律网络。我们将使用NIAAA的高斌博士开发的简单乙醇暴饮模型和我们独特的SHP-/-小鼠在不同的环境线索（光/暗周期）下。通过下一代rna测序分析酒精狂欢调节的肝脏中基因的节律性表达，通过GC/MS代谢组学分析确定血浆和肝脏代谢物的日变化。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。这项研究将为建立肝脏/中枢时钟与酒精性脂肪肝之间的关键联系提供必要的基础知识。因此，提出的创新研究有望使ALD研究取得实质性进展，使该项目具有很高的临床意义，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.