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Role of adipocyte gene expression regulation by Zfp407 in adipocyte biology and metabolic disease

Zfp407 脂肪细胞基因表达调控在脂肪细胞生物学和代谢疾病中的作用

基本信息

批准号：
10611358
负责人：
DAVID A BUCHNER
金额：
$ 40万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611358
关键词：
Adipocytes Adipose tissue Adult Binding Biochemical Biological Assay Biology Cells ChIP-seq Clinical Complement Complex DNA Data Development Disease Fatty acid glycerol esters Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomic approach Health Insulin Knock-out Knockout Mice Knowledge Link Lipids LoxP-flanked allele Measures Mediating Messenger RNA Metabolic Metabolic Diseases Metabolism Molecular Molecular Analysis Mus Non-Insulin-Dependent Diabetes Mellitus Nutritional Obesity Organism PPAR gamma Pathogenesis Pathway interactions Physiological Process Proteins RXR Regulation Role Signal Transduction Site Stimulus Structure Tamoxifen Techniques Testing Therapeutic Tissues Transcriptional Regulation Zinc Fingers adipocyte biology adipocyte differentiation adipokines blood glucose regulation cofactor experimental study global health global run on sequencing glucose uptake improved in vivo insight insulin sensitivity knock-down lipid biosynthesis lipid metabolism loss of function mRNA Stability metabolic phenotype new therapeutic target novel obesogenic precursor cell protein protein interaction response small hairpin RNA transcription factor transcriptome translational potential

项目摘要

Project Summary Adipocytes serve as the body’s primary site for lipid storage and act as signaling centers to coordinate the physiological response to an organism’s nutritional and metabolic state. A better understand of the molecules underlying adipocyte regulation and function will improve our knowledge of the pathophysiology of obesity and type 2 diabetes, which are associated with altered adipocyte function. This proposal will define the metabolic and molecular effects of a poorly understood transcription factor, Zfp407, that was recently identified by our lab as a critical molecule for adipocyte function and insulin sensitivity. We showed that Zfp407 deficiency has broad effects on adipocyte gene expression and results in reduced fat mass, illustrating the critical role of Zfp407 in adipose biology. However, the detailed physiological significance of Zfp407 and cellular mechanisms underlying them remain poorly understood. We propose three Aims to identify the critical physiological role of Zfp407 in differentiating and mature adipocytes and to determine the molecular mechanism by which Zfp407 controls gene expression in adipocytes. In Specific Aim 1, we will discover the physiological function of Zfp407 in mature adipocytes by testing whether constitutive and temporal deletion of Zfp407 in adipocytes alters adipocyte number, survival, and function and determining the metabolic consequences under normal and obesogenic conditions. In Specific Aim 2, we will elucidate the role and mechanism of Zfp407 in the differentiation of white, brown, and beige adipocytes. In Specific Aim 3, we will determine the molecular mechanism by which Zfp407 regulates the adipocyte transcriptome via PPARγ-dependent and PPARγ-independent mechanisms by combining state-of-the-art genomic approaches such as GRO-Seq and BRIC-Seq with classic biochemical techniques. Collectively, these studies will improve our mechanistic understanding of how the regulation of gene expression controls adipocyte differentiation and function. These data will improve our understanding of the pathophysiology of metabolic disease and may identify new translational opportunities for treating obesity and type 2 diabetes.

项目摘要脂肪细胞作为身体的主要网站的脂质储存和作为信号中心协调对有机体的营养和代谢状态的生理反应。更好地理解本脂肪细胞调节和功能的基础分子将提高我们对肥胖和2型糖尿病的病理生理学，这与脂肪细胞功能改变有关。这项提议将定义一个知之甚少的转录因子的代谢和分子效应， Zfp 407是本实验室最近发现的脂肪细胞功能和胰岛素的关键分子，灵敏度我们发现Zfp 407缺陷对脂肪细胞基因表达有广泛的影响，导致脂肪量减少，说明Zfp 407在脂肪生物学中的关键作用。但 Zfp 407的详细生理学意义和它们背后的细胞机制仍然很差明白我们提出了三个目的来确定Zfp 407在分化中的关键生理作用。并确定Zfp 407控制基因的分子机制在脂肪细胞中的表达。在具体目标1中，我们将发现Zfp 407的生理功能，通过测试脂肪细胞中Zfp 407的组成性和时间性缺失是否改变脂肪细胞数量、存活率和功能，并确定正常情况下的代谢结果。和致肥条件。在具体目标2中，我们将阐明Zfp 407在以下方面的作用和机制：白色、棕色和米色脂肪细胞的分化。在具体目标3中，我们将确定 Zfp 407通过PPARγ依赖性调节脂肪细胞转录组的分子机制通过结合最先进的基因组方法，使用经典生物化学技术的GRO-Seq和BRIC-Seq。总的来说，这些研究将改善我们对基因表达调控如何控制脂肪细胞的机械理解分化和功能。这些数据将提高我们对糖尿病的病理生理学的理解。代谢疾病，并可能确定新的翻译机会，用于治疗肥胖和2型糖尿病。糖尿病