The overall goal of Dr. Cohens research is to study the role of nuclear corepressors in thyroid hormone action. In addition, the role of corepressors in islet cell development and gene regulation has also been initiated. The thyroid hormone (TR) and retinoic acid (RAR) receptors bind the nuclear corepressors, including NCoR (nuclear corepressor protein) and SMRT (silencing mediator for retinoid and thyroid hormone receptors), in the absence of their respective ligands. NCoR and SMRT contain C-terminal interaction domains (IDs) containing the consensus sequence I/L-x-x-I/V-I (CoRNR box). My work has demonstrated that TR1 preferentially interacts with NCoR, whereas RARa prefers SMRT. This is due to the preferential interactions of the proximal IDs within NCoR and SMRT. We have also demonstrated that this preference is due, in part, to the presence of a unique domain in NCoR, not present in SMRT; this domain is specific for TR and does not bind RAR. Our data also suggests that the presence of two interacting domains is necessary for full interactions with nuclear receptors in cells. In addition, while the exact CoRNR box sequence of the SMRT ID is critical for recruitment of SMRT by RAR, the CoRNR box sequences themselves do not explain the strong interactions of the NCoR N2 domain with TR. Additional regions distal to this region are needed for optimal binding. Research is ongoing to study the role of the corepressors in negative regulation by thyroid hormone, and studies are being initiated to investigate corepressor function in the islet, specifically the pancreatic -cell.