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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和成年后的生理活动是必不可少的。此外，TH信号的特异性靶向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。虽然循环中的甲状腺激素水平被用来解释人类的甲状腺状况，但它们只是冰山一角，因为细胞TH的可获得性受转运体、脱碘酶和甲状腺激素受体亚型(TRs)的共同调节。因此，TH的细胞作用可以从特定组织中循环的TH水平中分离出来。我们先前已经证明，核辅阻遏子NCoR1和SMRT是细胞TH活动的关键调节因子，它们通过调节甲状腺功能减退症中可用配体的受体的敏感性以及抑制或抑制基因表达的能力来调节细胞TH活动。然而，NCoR1/SMRT或其他潜在辅抑制子发挥作用的完整机制仍有待确定。为了进一步了解核辅阻遏子的作用，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如何在它们与核受体的相互作用中，在它们被重新招募到基因组的背景下介导特异性。在第二个目标中，我们将确定与NCoR1/SMRT无关的TRs用于在甲状腺功能减退症或甲状腺激素抵抗综合征中调节抑制的新途径。最后，在第三个目标中，我们将探索为什么在成年生活中NCoR1和SMRT的缺失会导致直接的死亡。我们假设NCoR1/SMRT在调节营养供应方面有多余的作用。这些目标的共同完成将为NCOR1和SMRT如何潜在的其他辅抑制子具有调节甲状腺激素作用和代谢功能的功能，并在治疗代谢性疾病中开辟了针对这些途径的新途径。