GENOMIC ANALYSIS OF THE SRC FAMILY OF COREGULATORS IN TISSUE METABOLISM

组织代谢中核心调节因子 SRC 家族的基因组分析

基本信息

批准号：
7477176
负责人：
Francesco John DeMayo
金额：
$ 34.96万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7477176
关键词：
Ablation Acute Animals Bioinformatics Biological Assay Calories Class Condition Defect Development Elements Environment Epidemic Family Family member Fatty acid glycerol esters Food Funding Gene Expression Gene Expression Regulation Gene Targeting Generations Genes Genetic Genetic Transcription Genetically Engineered Mouse Genomics Goals Hepatic Homeostasis Individual Laboratories Lead Liver MYBBP1A gene Metabolic Metabolic Pathway Metabolism Microarray Analysis Molecular Morbidity - disease rate Mus Muscle Obesity Obesity associated disease Organ Overweight Pathway interactions Phenotype Physical activity Physiological Processes Physiology Play Promoter Regions Regulation Research Personnel Role Steroid Receptors Tamoxifen Technology Time Tissues Transcription Regulatory Protein Transfection United States Weight blood glucose regulation chromatin immunoprecipitation density gene function hormone regulation in vivo lipid biosynthesis mouse model postnatal programs promoter research study steroid hormone transcription factor

项目摘要

Obesity and the diseases associated with this condition are the leading cause of morbidity in the United States. The increase in the percentage of overweight individuals over the last two decades has made obesity and associated diseases an epidemic in the United States. Defining the molecular mechanisms regulating energy storage and utilization will lead to more effective ways of treating and controlling obesity. Over the last decade, a new class of transcription regulatory proteins, the coregulators has been shown to play a critical role in the regulation of metabolism. These coactivators exert a higher level of control over transcription by modulating the activity of a network of transcription factors regulating physiological processes. The coactivator family being investigated by this PPG is the p160 class of coregulators, the Steroid Receptor Coactivator family (SRC). Members of this family have been shown to be critical in the regulation of energy conservation and adipogenesis. Over the last funding period, we have used genetically engineered mouse models (GEMMs) in combination with high density DMA microarray technology to identify how the SRCs modulate steroid hormone regulation of gene expression. In the course of this analysis, we have identified specific genes in the liver whose expression is altered by the ablation of SRC-2/TIF2 and SRC-1. The metabolic pathways in which these genes function correlate with the observed metabolic phenotype and define the molecular pathways altered by the ablation of SRC-2/TIF2 and SRC-1. The goal of this proposal will be to investigate the contribution of hepatic SRC-2/TIF2 and SRC-1 in regulation of glucose and fat utilization. This proposal will identify the transcriptional network coordinated by these coactivators in the regulation of hepatic physiology. This will be accomplished by achieving the following specific aims: 1. The role of hepatic SRC-2/TIF2 and SRC-1 in regulating energy homeostasis will be investigated. 2. The primary target genes regulated by the SRC-2/TIF2 and SRC-1 genes in the liver will be defined. 3. The network of transcription factors regulated by SRC-2/TIF2 and SRC-1 will be identified using bioinformatics and molecular approaches in order to identify transcription factor networks dependent upon SRC-2/TIF2 and SRC-1. 4. The consequences of double hepatic ablation of SRC-2/TIF2 and SRC-1 in the regulation of energy and weight homeostasis will be investigated.

肥胖和与肥胖相关的疾病是美国发病的主要原因国家。过去二十年中超重个体比例的增加导致肥胖以及相关疾病在美国流行。定义调节的分子机制能量的储存和利用将带来更有效的治疗和控制肥胖的方法。超过过去十年，一类新的转录调节蛋白，即辅助调节蛋白，已被证明发挥着在代谢调节中发挥重要作用。这些共激活剂对通过调节转录因子网络的活性来调节生理转录流程。该 PPG 正在研究的共激活剂家族是 p160 类核心调节剂，即类固醇受体辅激活剂家族（SRC）。这个家庭的成员已被证明在能量保存和脂肪生成的调节。在上一个资助期间，我们使用了基因工程小鼠模型 (GEMM) 结合高密度 DMA 微阵列技术来识别 SRC 如何调节类固醇激素对基因表达的调节。在这个分析过程中，我们已经确定了肝脏中的特定基因，其表达因 SRC-2/TIF2 的消融而改变，并且 SRC-1。这些基因发挥作用的代谢途径与观察到的代谢相关表型并定义因 SRC-2/TIF2 和 SRC-1 消融而改变的分子途径。目标该提案的目的是研究肝脏 SRC-2/TIF2 和 SRC-1 在调节中的贡献葡萄糖和脂肪的利用。该提案将确定由这些协调的转录网络肝脏生理调节中的共激活剂。这将通过实现以下目标来实现具体目标： 1. 肝脏SRC-2/TIF2和SRC-1在调节能量稳态中的作用将是调查了。 2.肝脏中SRC-2/TIF2和SRC-1基因调控的主要靶基因是定义的。 3. SRC-2/TIF2 和 SRC-1 调节的转录因子网络将使用生物信息学和分子方法，以确定转录因子网络依赖于 SRC-2/TIF2 和 SRC-1。 4. SRC-2/TIF2 和 SRC-1 双肝消融的后果将研究能量和体重稳态的调节。