Xenobiotic-responsive hepatic long non-coding RNAs

异生素反应性肝脏长非编码RNA

基本信息

批准号：
10058507
负责人：
DAVID J WAXMAN
金额：
$ 47.2万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10058507
关键词：
Abbreviations Address Adult Affect Agonist Architecture Automobile Driving Benzene Biological CRISPR interference Cell Nucleus Cells Chemical Exposure Chemicals Chromatin Chromatin Loop Cirrhosis Clustered Regularly Interspaced Short Palindromic Repeats Code Complex Deoxyribonucleases Dependovirus Development Diagnosis Diet Disease Disease Progression Environment Environmental Pollutants Enzymes Epigenetic Process Etiology Evaluation Event Exposure to Fatty Liver Gene Expression Gene Targeting Genes Genetic Transcription Genome Genomics Guide RNA Health Hepatic Hepatic lobule Hepatocyte High Fat Diet Human Hypersensitivity Industrialization Inflammation Knock-out Knockout Mice Lead Ligands Link Liver Liver Cirrhosis Liver Failure Liver diseases Lobule Mediator of activation protein Metabolic Pathway Metabolism Mitochondria Modeling Mus Nuclear Nuclear Pore Complex Nuclear Receptors Orthologous Gene PPAR alpha Pathologic Pathology Pathway Analysis Pathway interactions Physiological Processes Positioning Attribute Primary carcinoma of the liver cells Process Proteins Regulator Genes Research Role Serotyping Site Small Nuclear RNA Specificity Structure Testing Time Tissues Untranslated RNA Work Xenobiotic Metabolism Xenobiotics activating transcription factor advanced disease base blood glucose regulation carbohydrate metabolism cell type constitutive androstane receptor endonuclease environmental chemical environmental chemical exposure in vivo insight interest lipid biosynthesis lipid metabolism liver development liver metabolism mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel marker pregnane X receptor prevent promoter receptor therapeutic target transcription factor transcription termination transcriptome transcriptome sequencing transcriptomics

项目摘要

7. Project Summary/Abstract Many industrial chemicals, environmental pollutants and other xenochemicals activate transcription factors belonging to the nuclear receptor superfamily, which leads to widespread genomic, epigenetic and transcriptional changes that disrupt key biological pathways and metabolic processes in liver and other tissues. The studies proposed focus on the liver nuclear receptor CAR (Constitutive Androstane Receptor; NR1I3), which is activated by structurally diverse xenochemicals and regulates transcription of hundreds of protein-coding genes important for processes such as xenobiotic metabolism, lipogenesis, glucose homeostasis, and inflammation, and has been implicated as a regulator of non-alcoholic fatty liver disease (NAFLD) development. We have discovered that xenobiotic agonists of CAR and other xenobiotic-responsive receptors induce or repress the transcription of several hundred nuclear-enriched long non-coding RNAs (lncRNAs) with epigenetic and gene regulatory potential, many of which have human orthologs. This proposal builds on these findings and on recent advances in liver cell zonation, single cell-based transcriptomic profiling, and gene co-expression network analysis to elucidate in an intact mouse liver model the effects of CAR-responsive lncRNAs on fatty liver disease induced by foreign chemical exposure. The studies proposed test the hypothesis that a subset of CAR-responsive lncRNAs control hepatic gene regulatory networks driving NAFLD and downstream pathologies, dysregulating processes such as lipid and carbohydrate metabolism, hepatic architecture and mitochondrial function in a liver cell type-specific and hepatic lobule zone-dependent manner. The work proposed uses TCPOBOP (1,4-bis[2-(3,5-dichloro-pyridyloxy)]benzene), a prototypic non- genotoxic chemical and CAR-specific agonist ligand, to address the seemingly paradoxical finding that persistent exposure to foreign chemical CAR activators induces NAFLD in mice fed normal chow diet, but suppresses NAFLD development in mice fed a high fat diet. These studies will elucidate the role of CAR, and the lncRNAs that it regulates, in fatty liver disease etiology and progression. Results obtained will give critical insight into the underlying mechanisms by which foreign chemicals dysregulate CAR-dependent metabolic pathways linked to NAFLD, which affects 25% of US adults and is a major cause of cirrhosis, hepatocellular cancer and liver failure. This work will refocus research efforts on xenochemical action to include mechanistic studies of single cell-based, spatially zonated gene regulatory networks and the non-coding transcriptome, and will serve as a paradigm for other foreign chemical-activated receptors that dysregulate gene expression in complex ways. Together, the proposed studies on CAR-responsive lncRNAs and their role in xenochemical- induced liver pathology may lead to new ways to prevent, diagnose or treat liver diseases induced by chemical exposure.

7. 项目总结/摘要许多工业化学品、环境污染物和其他异种化学物质都会激活转录因子属于核受体超家族，导致广泛的基因组、表观遗传和转录变化会破坏肝脏和其他部位的关键生物途径和代谢过程组织。研究建议重点关注肝脏核受体 CAR（组成型雄甾烷受体；Constitutive Androstane Receptor； NR1I3），由结构多样的异种化学物质激活并调节数百种基因的转录对外源代谢、脂肪生成、葡萄糖等过程很重要的蛋白质编码基因体内平衡和炎症，并被认为是非酒精性脂肪肝疾病的调节者（NAFLD）的发展。我们发现 CAR 的异生素激动剂和其他异生素响应剂受体诱导或抑制数百个核富集的长非编码RNA的转录（lncRNA）具有表观遗传和基因调控潜力，其中许多具有人类直向同源物。这个提议基于这些发现以及肝细胞分区、基于单细胞的转录组学的最新进展分析和基因共表达网络分析，以阐明在完整的小鼠肝脏模型中的影响对外来化学物质暴露引起的脂肪肝疾病的 CAR 响应性 lncRNA。提出的研究检验以下假设：CAR 响应性 lncRNA 子集控制驱动肝基因调控网络 NAFLD 和下游病理、脂质和碳水化合物代谢等过程失调，肝细胞类型特异性和肝小叶区域依赖性的肝结构和线粒体功能方式。拟议的工作使用 TCPOBOP（1,4-双[2-(3,5-二氯吡啶氧基）]苯），一种原型非基因毒性化学物质和 CAR 特异性激动剂配体，以解决看似矛盾的发现持续接触外来化学 CAR 激活剂会在正常饮食的小鼠中诱发 NAFLD，但是抑制高脂肪饮食小鼠 NAFLD 的发展。这些研究将阐明 CAR 的作用，以及它在脂肪肝疾病的病因学和进展中调节的lncRNA。获得的结果将给出关键的深入了解外来化学物质失调 CAR 依赖性代谢的潜在机制与 NAFLD 相关的途径，NAFLD 影响 25% 的美国成年人，是肝硬化、肝细胞性肝病的主要原因癌症和肝功能衰竭。这项工作将重新集中研究异种化学作用，包括机械作用基于单细胞的空间分区基因调控网络和非编码转录组的研究，并将作为其他外来化学激活受体失调基因表达的范例以复杂的方式。总之，关于 CAR 响应性 lncRNA 及其在异种化学中的作用的拟议研究诱发性肝脏病理学可能会带来预防、诊断或治疗化学物质诱发的肝脏疾病的新方法接触。