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Corepressor regulation of nuclear receptor action

核受体作用的辅阻遏物调节

基本信息

批准号：
9701510
负责人：
ANTHONY N HOLLENBERG
金额：
$ 66.99万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9701510
关键词：
Adult Affect Cell Survival Cells Cessation of life Compensation Complex Data Development Embryo Equilibrium Gene Expression Genes Genetic Transcription Genome Genomics Hepatic Hepatocyte Histone Deacetylase Human Hypoglycemia Hypothyroidism Intestines Iodide Peroxidase Life Ligands Liver Mediating Metabolic Metabolic Diseases Metabolism Molecular Conformation Multiprotein Complexes Mus Mutation NCOR1 gene Nuclear Nuclear Receptors Nutrient Nutrient availability Nutritional Nutritive Value Pathway interactions Physiological Physiological Processes Play Process Protein Isoforms Proteins Regulation Repression Resistance Retinoic Acid Receptor Role SMRT protein Signal Transduction Specificity Syndrome Techniques Testing Thyroid Gland Thyroid Hormone Receptor Thyroid Hormone Receptor Gene Thyroid Hormones Time Tissues Work antagonist cell type experimental study gene repression genetic corepressor hormonal signals hormone response element hormone sensitivity hypercholesterolemia improved in silico in vivo insight mouse model natural hypothermia nonalcoholic steatohepatitis novel postnatal programs protein function receptor receptor binding receptor function recruit

项目摘要

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.

甲状腺激素 (TH) 调节许多关键的生理过程，这些过程对于正常发育以及成年后的生理活动至关重要。此外，TH 信号传导的特异性靶向可能会改善代谢性疾病，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用于解释人类的甲状腺状态，但它们只是冰山一角，因为细胞 TH 的可用性受到转运蛋白、脱碘酶和甲状腺激素受体亚型 (TR) 共调节剂的调节。因此，TH 的细胞作用可以与特定组织中的循环 TH 水平无关。我们之前已经证明，核辅抑制因子 NCoR1 和 SMRT 通过调节 TR 对可用配体的敏感性以及 TR 沉默或抑制甲状腺功能减退症基因表达的能力，是细胞 TH 作用的关键调节因子。然而，NCoR1/SMRT 或其他潜在辅阻遏物发挥作用的完整机制仍有待确定。为了进一步了解核辅抑制作用，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 在招募到基因组的背景下如何介导它们与核受体相互作用的特异性。在第二个目标中，我们将确定 TRs 采用的新途径，独立于 NCoR1/SMRT 来介导甲状腺功能减退症或甲状腺激素抵抗综合征的抑制。最后，在第三个目标中，我们将探讨为什么在成年生活中失去 NCoR1 和 SMRT 会导致立即死亡。我们假设 NCoR1/SMRT 在调节营养可用性方面具有冗余作用。共同完成这些目标将为了解 NCOR1 和 SMRT 如何潜在的其他辅抑制因子可以调节甲状腺激素的作用和代谢功能，并为靶向这些途径治疗代谢疾病开辟新途径。