GENOMIC ANALYSIS OF THE SRC FAMILY OF COREGULATORS IN TISSUE METABOLISM

Baylor College Of Medicine, Houston TX

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Abstract

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