Nuclear Receptor Coregulator Functional Pathology in Metabolic Disease

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NRs function by interacting with coregulators, including corepressors such as N-CoR and SMRT that interact with unliganded NRs, and corepressors such as RIP140 that interact with liganded NRs. The corepressors, in turn, recruit histone deacetylase (HDAC) to the NR-bound target genes. Here we propose to determine the role of coregulators in regulating gene expression in cells that are pathologically affected in metabolic disease, namely adipocytes and liver. Specifically, this project proposes the generation and validation of coregulator knockdown reagents in adipocytes and mouse liver, the determination of the extent and integration of corepressor regulation of gene expression in adipocytes, and determining the extent and integration of corepressor regulation of gene expression in mouse liver.