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Nuclear Repressors in Genomic Control of Healthful Obesity

健康肥胖基因组控制中的核抑制因子

基本信息

批准号：
10490465
负责人：
Grant D Barish
金额：
$ 43.82万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-10 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10490465
关键词：
Ablation Acetylation Adipocytes American BCL6 gene Bile Acids Binding ChIP-seq Chromatin Chromatin Loop Complication Consensus Coupled DNA Disease Disease susceptibility Energy Metabolism Estrogen Receptor alpha Exhibits Fatty acid glycerol esters Female Fibrosis GPBAR1 gene GTP-Binding Proteins Gene Expression Genes Genetic Engineering Genetic Transcription Genomics Hepatic Hepatocyte Histones Lead Ligation Link Lipids Liver Lysine Maps Masculine Metabolic Metabolic Diseases Metabolism Molecular Molecular Genetics Morbidity - disease rate Mus Nuclear Obesity Overnutrition PPAR alpha Pathway interactions Phase Physiological Play Production Regulation Regulator Genes Resolution Risk Role Sex Bias Signal Transduction Site Sterols Structure of germinal center of lymph node Switch Genes Testing Therapeutic Up-Regulation Work biological sex end stage liver disease experimental study fatty liver disease gain of function gene network gene repression glucose tolerance histone modification in vivo insight loss of function male men mutant non-alcoholic fatty liver disease nonalcoholic steatohepatitis overexpression oxidation receptor recruit sex sexual dimorphism subcutaneous transcription factor transcriptomics virtual

项目摘要

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) afflicts nearly a quarter of Americans and is projected to become the leading cause of end-stage liver disease in the next decade. It is driven by overnutrition, disproportionately occurs in men, and is linked to derangements in liver lipid and sterol metabolism. The molecular determinants that control NAFLD and its sex-bias are incompletely understood. Using conditional genetic engineering, we have identified a profound role for the transcription factor B cell lymphoma 6 (BCL6) to direct sexually dimorphic transcription in hepatocytes. Herein, we propose to comprehensively dissect the transcriptional regulatory mechanisms of BCL6 underlying its sex-specific programming and the functional implications of hepatocyte Bcl6 on fatty liver disease and whole body metabolism. In Aim 1, we will test the impact of BCL6 on chromatin looping and histone modification, its sex-specific modes of recruitment to chromatin, and coregulation with estrogen receptor alpha. In Aim 2, we define the functional role of Bcl6 in the sexual dimorphism of NAFLD, its signaling through bile acid pathways, and its impact on fibrosis using loss- and gain-of-function studies in vivo. Together, these studies will reveal new molecular insights into the regulation of sexually dimorphic transcription and NAFLD.

项目总结非酒精性脂肪性肝病(NAFLD)困扰着近四分之一的美国人，预计将成为未来十年终末期肝病的主要原因。它是由营养过剩驱动的，不成比例地发生在男性中，并与肝脏脂肪和类固醇代谢紊乱有关。这些分子决定因素控制非酒精性脂肪肝及其性别偏见的研究还不完全清楚。使用条件基因工程，我们有发现转录因子B细胞淋巴瘤6(BCL6)在指导性二型性方面发挥着深远的作用肝细胞中的转录。在这里，我们建议全面剖析转录调控 BCL6的性别特异性编程机制及肝细胞BCL6的功能意义论脂肪肝与全身新陈代谢。在目标1中，我们将测试BCL6对染色质环路的影响和组蛋白修饰，其性别特异性的重新聚集到染色质的方式，以及与雌激素的共同调节受体阿尔法。在目标2中，我们定义了bcl6在NAFLD的性别二型性中的功能作用，它的信号转导通过胆汁酸途径，以及它对体内功能丧失和功能获得的研究对纤维化的影响。一起，这些研究将揭示对性二态转录和调控的新的分子见解 NAFLD。