Corepressor regulation of nuclear receptor action

甲状腺激素（TH）调节许多关键的生理过程，这些生理过程对正常发育和成年期的生理活动至关重要。此外，特异性靶向TH信号可能改善代谢性疾病，包括高胆固醇血症和非酒精性脂肪性肝炎。虽然循环甲状腺激素水平在人类中被用来解释甲状腺状态，但它们只是冰山一角，因为细胞TH的可用性是由转运体、去碘酶和甲状腺激素受体异构体（TRs）的共调节剂调节的。因此，TH的细胞作用可以与特定组织中的循环TH水平分离。我们之前已经证明核共抑制因子NCoR1和SMRT是细胞TH作用的关键调节因子，通过调节TR对可用配体的敏感性和TR沉默或抑制甲状腺功能减退症基因表达的能力。然而，NCoR1/SMRT或其他潜在的共抑制因子的完整机制仍有待确定。为了进一步了解核共抑制子的作用，我们提出了三个具体目标。在第一个目标中，我们将确定NCoR1和SMRT如何在其招募到基因组的背景下与核受体相互作用中介导特异性。在第二个目标中，我们将确定TRs使用的独立于NCoR1/SMRT的新途径，以介导甲状腺功能减退或甲状腺激素抵抗综合征的抑制。最后，在第三个目标中，我们将探讨为什么NCoR1和SMRT在成人生活中丢失会导致立即死亡。我们假设NCoR1/SMRT在调节营养可利用性方面具有冗余作用。这些目标的共同完成将为NCOR1和SMRT提供关键的见解

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.