The thyroid hormone receptor (TR) isoforms are members of nuclear receptor superfamily. They regulate target genes both positively and negatively in the presence and absence of their ligand T3, which is essential for normal mammalian development and function. Ligand-independent function of the TR is mediated by two large proteins, NCoR and SMRT, termed nuclear corepressors, which in turn recruit a multiprotein complex which mediates gene silencing on positive thyroid hormone response elements (TREs). The addition of ligand causes the TR binding complex to release the corepressor and recruit coactivators to mediate further gene activation. NCoR and SMRT have significant homology at the amino acid level but differ substantially in sequence and structure in key regions important for TR interaction and repressing function. These differences, despite the similar distinct biological roles. It is unclear which corepressor is important in thyroid hormone action but it is likely that one or both play critical roles in hypothyroidism and Resistance to Thyroid Hormone (RTH). Thus, an understanding of the mechanisms by which the nuclear corepressors interact with thyroid hormone signaling pathways will shade new light on basic mechanisms by which the TRs regulate gene expression and on the role of the ligand-independent activity of the TR in human disease. The first aim of this proposal will focus on the nuclear receptor interacting domains of NCoR and SMRT in order to support the hypothesis that corepressor specificity exists and that the TR prefers to interact with NCoR. The second aim will allow for the direct testing of corepressor specificity in mammalian cells. The third aim will employ mouse models that lack functional NCoR to explore the role of the corepressors in hypothyroidism and RTH as well as to further address the role of NCoR directly in thyroid hormone action. Together, completion of these aims will lend significant insight into the role of the nuclear receptor proteins on thyroid hormone action and establish a role for these proteins in thyroid disease. Furthermore, given the growing importance of corepressor interactions in other signaling systems, the proposed studies will also shed insight into other areas of human biology.