SRC FAMILY OF COREGULATORS IN TISSUE METABOLISM

肥胖及其相关疾病是美国发病率的主要原因。 各州。在过去的二十年里，超重个体比例的增加导致了肥胖 以及相关疾病在美国是一种流行病.明确调控的分子机制 能量的储存和利用将导致治疗和控制肥胖的更有效的方法。超过了 近十年来，一类新的转录调控蛋白--协同调控蛋白已被证明发挥着重要作用 在新陈代谢调节中的关键作用。这些共激活剂对 通过调节调节生理活动的转录因子网络的活性进行转录 流程。PPG正在研究的辅激活子家族是p160类辅调制子， 类固醇受体辅活化子家族(SRC)。这个家庭的成员已经被证明在 能量节约和脂肪生成的调控。在过去的资助期内，我们使用了基因 工程小鼠模型(GEMM)与高密度DMA微阵列技术相结合，以识别 SRCs如何调节类固醇激素对基因表达的调节。在这一分析过程中，我们 已经确定了肝脏中的特定基因，其表达因SRC-2/TIF2和TIF2的消融而改变 SRC-1。这些基因发挥作用的代谢途径与观察到的代谢相关。 并确定SRC-2/TIF2和SRC-1消融后改变的分子通路。目标是 本研究的目的是探讨肝脏SRC-2/TIF2和SRC-1在调节血管生成中的作用。 葡萄糖和脂肪的利用。这项提案将确定由这些组织协调的转录网络 肝生理调节中的辅活化子。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 调查过了。2.肝脏中受SRC-2/TIF2和SRC-1基因调控的主要靶基因为 已定义。3.SRC-2/TIF2和SRC-1调控的转录因子网络将通过 生物信息学和分子方法，以识别依赖于 SRC-2/TIF2和SRC-1。4.SRC-2/TIF2和SRC-1双肝切除对大鼠肝损伤的影响 能量和体重动态平衡的调节将被调查。

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.