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

• 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
• 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

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.

肥胖和与这种情况相关的疾病是联合发病率的主要原因 国家。过去二十年来超重个人百分比的增加使肥胖 相关疾病在美国流行。定义调节的分子机制 储能和利用将导致更有效的治疗和控制肥胖的方法。在 最近十年，一种新的转录调节蛋白，调节剂已显示出一种 在代谢调节中的关键作用。这些共激活因子对 通过调节调节生理的转录因子网络的活性来转录 过程。该PPG调查的共激活因子家族是P160类别的核心节， 类固醇受体共激活因子家族（SRC）。这个家庭的成员在 调节能量守恒和成生成。在最后的资金期间，我们已经使用了遗传 工程鼠标模型（GEMM）与高密度DMA微阵列技术结合使用 SRCS如何调节基因表达的类固醇激素调节。在此分析过程中，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 SRC-1。这些基因功能与观察到的代谢相关的代谢途径 表型并定义了通过SRC-2/TIF2和SRC-1的消融改变的分子途径。目标 该提案将是调查肝SRC-2/TIF2和SRC-1在调节中的贡献 葡萄糖和脂肪利用。该建议将确定由这些提案协调的转录网络 在调节肝生理学方面的共激活剂。这将通过实现以下内容来实现 具体目的：1。肝SRC-2/TIF2和SRC-1在调节能量稳态中的作用将是 调查。 2。肝脏中由SRC-2/TIF2和SRC-1基因调节的主要靶基因将是 定义。 3。将使用SRC-2/TIF2和SRC-1调节的转录因子网络。 生物信息学和分子方法，以识别基于转录因子网络 SRC-2/TIF2和SRC-1。 4。在src-2/tif2和src-1的双重肝脏消融的后果 将研究能量和体重稳态的调节。