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：
10210396
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/10210396
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 Expression Profile 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 epigenetic silencing 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。项目摘要/摘要许多工业化学品，环境污染物和其他Xenchemicals激活转录因子属于核受体超家族，这导致了广泛的基因组，表观遗传和转录变化破坏了肝脏和其他的关键生物学途径和代谢过程组织。研究提出，重点关注肝核受体车（组成型雄激素受体； NR1I3），它被结构上多样化的异种化学物激活，并调节数百个转录蛋白质编码基因对诸如异种生物代谢，脂肪生成，葡萄糖等过程很重要稳态和炎症，并被与非酒精性脂肪肝病的调节剂有关（NAFLD）发展。我们发现汽车和其他异种生物响应的异种生物激动剂受体诱导或抑制数百个富含核富含核的长无编码RNA的转录（LNCRNA）具有表观遗传和基因调节潜力，其中许多具有人类直系同源物。这个建议建立在这些发现以及肝细胞分区的最新进展基础上，基于单细胞的转录组分析和基因共表达网络分析，以在完整的小鼠肝脏中阐明模型外国化学暴露引起的脂肪肝疾病的汽车反应性LNCRNA。研究提出检验以下假设：CAR响应LNCRNA控制肝脏基因调节网络驱动的假设 NAFLD和下游病理，失调的过程（例如脂质和碳水化合物代谢），肝细胞特异性和肝叶区域依赖性肝细胞类型中的肝架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 - 遗传毒性化学和碳毒素特异性激动剂配体，以解决看似矛盾的发现，即持续暴露于外国化学汽车激活剂会诱导NAFLD喂养正常的食物饮食，但抑制喂养高脂饮食的小鼠的NAFLD发育。这些研究将阐明汽车的作用，并它在脂肪肝病的病因和进展中调节的LNCRNA。获得的结果将给予关键深入了解外国化学物质失调CAR依赖性代谢的潜在机制与NAFLD相关的途径，该途径影响美国成年人的25％，是肝硬化的主要原因癌症和肝衰竭。这项工作将重点关注Xenchemical Action的研究工作，以包括机械对单细胞的，空间分区的基因调节网络和非编码转录组的研究，并将作为其他外国化学激活受体的范式，这些受体失调基因表达以复杂的方式。共同提出了关于汽车响应性lncrNA及其在异种化学中的作用的研究诱导的肝脏病理可能会导致新的方法来预防，诊断或治疗化学诱导的肝脏疾病接触。