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：
10674915
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/10674915
关键词：
Ablation Acetylation Adipocytes American BCL6 gene Bile Acids Binding ChIP-seq Chromatin Chromatin Loop Complication Consensus DNA Disease Disease susceptibility Energy Metabolism Estrogen Receptor alpha Exhibits Fatty acid glycerol esters Female Fibrosis G-Protein-Coupled Receptors GPBAR1 gene Gene Expression Genes Genetic Genetic Engineering Genetic Transcription Genomics Hepatic Hepatocyte Histones Ligation Link Lipids Liver Lysine Maps Masculine Metabolic Metabolic Diseases Metabolism Molecular Morbidity - disease rate Mus Nuclear Obesity Overnutrition PPAR alpha Pathway interactions Phase Physiological Play Production Regulation Regulator Genes Repression 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.

项目摘要非酒精性脂肪肝病（NAFLD）遭受了近四分之一的美国人的困扰，预计将成为未来十年的终末期肝病的主要原因。它是由营养不良驱动的，发生不成比例在男性中，并且与肝脂质和固醇代谢的危险有关。分子决定因素控制NAFLD及其性别偏见尚不完全理解。使用条件基因工程，我们有鉴定出转录因子B细胞淋巴瘤6（BCL6）的重要作用，以指导性二态肝细胞中的转录。在此，我们建议全面剖析转录调节 BCl6的基础机制，其性别特异性编程和肝细胞BCl6的功能含义关于脂肪肝病和全身代谢。在AIM 1中，我们将测试BCL6对染色质环的影响和组蛋白的修饰，其特定性别的募集模式以及雌激素的核心调节受体α。在AIM 2中，我们定义了BCl6在NAFLD的性二态性中的功能作用，其信号传导通过胆汁酸途径及其对纤维化的影响，使用体内损失和功能性研究。一起，这些研究将揭示对性二态转录调节的新分子见解和 nafld。