Thyroid hormone (TH) regulates numerous key physiologic processes that are essential for normal development and then physiologic action in adulthood. Furthermore, specific targeting of TH signaling may improve metabolic disease, including hypercholesterolemia and non-alcoholic steatohepatitis. While circulating thyroid hormone levels are used in humans to interpret thyroid status they are just the tip of the iceberg as cellular TH availability is regulated by transporters, deiodinases, and coregulators of the thyroid hormone receptor isoforms (TRs). Thus, cellular action of TH can be disassociated from circulating TH levels in a particular tissue. We have previously shown that the nuclear corepressors, NCoR1 and SMRT are critical regulators of cellular TH action by regulating both the sensitivity of the TR for available ligand and the ability of the TR to silence or repress in gene expression in hypothyroidism. However, the full mechanism by which NCoR1/SMRT or other potential corepressors function remains to be determined. To gain further insight into nuclear corepressor action we propose three specific aims. In the first Aim we will determine how NCoR1 and SMRT mediate specificity in their interactions with nuclear receptors in context of their recruitment to the genome. In the second Aim we will identify novel pathways that the TRs employ, independent of NCoR1/SMRT to mediate repression in hypothyroidism or in the syndromes of resistance to thyroid hormone. Finally, in the third Aim we will explore why loss of NCoR1 and SMRT in adult life leads to immediate lethality. We hypothesize that NCoR1/SMRT have redundant roles in regulating nutrient availability. Together completion of these Aims will provide key insight into how NCOR1 and SMRT and potentially other corepressors function to regulate thyroid hormone action and metabolic function and open up new avenues to target these pathways in the treatment of metabolic disease.

Thyroid hormone (TH) regulates numerous critical processes in a wide variety of different cell types through its ability to target key genomic programs, central to its ability to act in such fashion is the ability of it cognate receptors, the thyroid hormone receptor isoforms, to interact with a wide variety of co-regulators including the nuclear corepressors, NCoR1 and SMRT. The function of NCoR1 and SMRT are critical to thyroid hormone receptor function by controlling its sensitivity to thyroid hormone and its function in the absence of thyroid hormone. In this proposal we will determine the mechanism of specificity of the corepressors for the thyroid hormone receptors, ask whether other corepressors besides NCoR1/SMRT function to regulate thyroid hormone action and finally understand the role of NCoR1/SMRT in regulating nutritional availability.