GENOMIC ANALYSIS OF THE SRC FAMILY OF COREGULATORS IN TISSUE METABOLISM

肥胖和与此相关的疾病是美国发病的主要原因。 States.在过去的二十年里，超重人群的比例增加， 和相关疾病在美国流行。定义调节的分子机制 能量储存和利用将导致治疗和控制肥胖症的更有效的方法。来 近十年来，一类新的转录调节蛋白，辅调节蛋白已被证明在转录过程中起着重要作用。 在调节新陈代谢中起着关键作用。这些共激活因子对细胞的生长和分化发挥更高水平的控制作用。 通过调节调节生理活性的转录因子网络的活性， 流程. PPG研究的共激活因子家族是p160类共调节因子， 类固醇受体辅激活因子家族（SRC）。这个家庭的成员已经被证明是关键的， 能量守恒和脂肪生成的调节。在上一个资助期内，我们使用了基因技术， 工程小鼠模型（GEMM）结合高密度DMA微阵列技术， SRCs如何调节类固醇激素对基因表达的调节。在分析过程中，我们 已经确定了肝脏中的特定基因，其表达因SRC-2/TIF 2的消融而改变， SRC-1这些基因发挥功能的代谢途径与观察到的代谢途径相关。 表型和定义由SRC-2/TIF 2和SRC-1的消融改变的分子途径。目标 这项建议的目的是研究肝脏SRC-2/TIF 2和SRC-1在调节肝脏细胞凋亡中的作用。 葡萄糖和脂肪的利用。这项建议将确定转录网络协调这些 在肝脏生理调节中的辅助激活剂。这将通过实现以下目标来实现 具体目标：1.肝SRC-2/TIF 2和SRC-1在调节能量稳态中的作用将被进一步研究。 研究了2.在肝脏中由SRC-2/TIF 2和SRC-1基因调节的主要靶基因将是 定义了3. SRC-2/TIF 2和SRC-1调控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/TIF 2和SRC-1。4. SRC-2/TIF 2和SRC-1的双重肝消融术的结果 将研究能量和体重稳态的调节。

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.