GENOMIC ANALYSIS OF THE SRC FAMILY OF COREGULATORS IN TISSUE METABOLISM

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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.