Thyroid Hormone Receptors in Health and Disease

健康和疾病中的甲状腺激素受体

• 批准号: 8937662
• 负责人: SHEUE-YANN CHENG
• 金额: $ 74.47万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8937662
• 关键词: Acetylation; Adult; Affect; Binding; Biological Process; Bone Development; CCAAT-Enhancer-Binding Protein-alpha; Complex; Constipation; DNA Sequence; Deacetylation; Development; Developmental Delay Disorders; Differentiation and Growth; Disease; Disease model; Dominant-Negative Mutation; Dose; Exhibits; Family; Feedback; Female; Gene Targeting; Genes; Genetic Transcription; Growth; Health; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Human; Hypothalamic structure; Hypothyroidism; Individual; Investigation; Ligands; Mediating; Messenger RNA; Molecular; Morphology; Mus; Mutate; Mutation; NCOR1 gene; Nuclear Receptors; Outcome; PPAR gamma; Patients; Phenotype; Physiologic calcification; Physiological; Pituitary Gland; Protein Isoforms; Proteins; Reporting; Resistance; Role; Serum; Severities; Skeleton; Symptoms; THRA gene; THRB gene; Testing; Therapeutic; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Thyroid hormone receptor alpha; Thyrotropin; Thyroxine; Time; Tissues; Triiodothyronine; Vorinostat; base; bone; bone mass; bone strength; chromatin immunoprecipitation; hormone response element; improved; in vivo; lipid biosynthesis; mouse model; mutant; promoter; response; skeletal; skeletal abnormality; skeletal dysplasia; transcription factor; treatment response

1). A histone deacetylase inhibitor improves hypothyroidism caused by a TRalpha1 mutant Using a mouse model of hypothyroidism caused by a dominant negative TRalpha1PV mutant and its derived mouse model harboring a mutated nuclear receptor corepressor (NCOR1deltaID) (TRalpha1PV/+Ncor1deltaID mice), we recently showed that aberrant release of TRalpha1 mutants from the NCOR1 repressor complex mediates dominant negative actions of TRalpha1 mutants in vivo. We tested the hypothesis that deacetylation of nucleosomal histones associated with aberrant recruitment of corepressors by TRalpha1 mutants underlies pathological phenotypic expression. We treated TRalpha1PV/+ mice and TRalpha1PV/+Ncor1deltaID mice with a histone deacetylase (HDAC) inhibitor, SAHA. SAHA significantly ameliorated the impaired growth, bone development, and adipogenesis of TRalpha1PV/+ mice. In TRalpha1PV/+Ncor1deltaID mice, SAHA improved these abnormalities even further. We focused our molecular analyses on how SAHA improved the impaired adipogenesis leading to the lean phenotype. We found that SAHA reverted the impaired adipogenesis by de-repressing the expression of the two master regulators of adipogenesis, CCAAT/enhancer-binding protein alpha gene and peroxisome-proliferator activated receptor gamma, as well as other adipogenic genes at both the mRNA and protein levels. Chromatin immunoprecipitation analyses indicated SAHA increased the extent of acetylation of nucleosomal H4K5 and H3 to re-activate adipogenic genes to reverting adipogenesis. Thus, HDAC, confer in vivo aberrant actions of TRalpha1 mutants. Importantly, for the first time, the present studies show that HDAC inhibitors are clearly beneficial for hypothyroidism and could be therapeutics for treatment. 2). Thyroid hormone receptor alpha mutation causes a severe and thyroxine-resistant skeletal dysplasia In an attempt to improve developmental delay and alleviate symptoms of hypothyroidism caused by mutations of the THRA gene, patients are receiving varying doses and durations of L-thyroxine (T4) treatment but responses have been inconsistent so far. TRalpha1PV/+ mice express a similar potent dominant-negative mutant TRalpha1 to affected individuals, and thus represent an excellent disease model. We hypothesized that TRalpha1PV/+ mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supra-physiological dose of T4 ameliorates the skeletal abnormalities. Adult female TRalpha1PV/+ mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effect on skeletal maturation, linear growth or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bone stiffness and strength, suggesting the potential for detrimental consequences in the long-term. Our studies establish that TRalpha1 has an essential role in the developing and adult skeleton, and predict that patients with different THRA mutations will display variable responses to T4 treatment, which depend on the severity of the causative mutation.

1）。 A histone deacetylase inhibitor improves hypothyroidism caused by a TRalpha1 mutant Using a mouse model of hypothyroidism caused by a dominant negative TRalpha1PV mutant and its derived mouse model harboring a mutated nuclear receptor corepressor (NCOR1deltaID) (TRalpha1PV/+Ncor1deltaID mice), we recently showed that aberrant release of TRalpha1来自NCOR1抑制剂复合物的突变体介导了体内tralpha1突变体的主要负作用。我们检验了以下假设：与tralpha1突变体相对于异常募集的核小体组蛋白脱乙酰化是病理表型表达的基础。我们用组蛋白脱乙酰基酶（HDAC）抑制剂SAHA治疗了Tralpha1pv/+小鼠和Tralpha1pv/+ Ncor1deltaid小鼠。 SAHA显着改善了Tralpha1pv/+小鼠的生长，骨发育和成脂的受损。在tralpha1pv/+ncor1deltaid小鼠中，SAHA进一步改善了这些异常。我们将分子分析集中在SAHA如何改善导致瘦表型的脂肪生成受损的情况下。我们发现，Saha通过去抑制脂肪形成，CCAAT/增强子结合蛋白α基因和过氧化物酶体增生剂激活的受体伽玛以及MRNA和蛋白质水平的其他脂源基因的表达来恢复受损的脂肪形成。染色质免疫沉淀分析表明，SAHA增加了核小体H4K5和H3的乙酰化程度，以重新激活掺杂基因以恢复脂肪生成。因此，HDAC赋予tralpha1突变体的体内异常作用。重要的是，本研究首次表明HDAC抑制剂显然对甲状腺功能减退症有益，并且可以治疗治疗。 2）。甲状腺激素受体α突变会导致严重和甲状腺抗性的骨骼发育不良，以试图改善发育迟缓并减轻THRA基因突变引起的甲状腺功能减退症状的症状，患者正在接受L-甲状腺素（T4）治疗的不同剂量和持续时间，但反应率很少。 tralpha1pv/+小鼠对受影响的个体表达了类似的有效的显性阴性突变体Tralpha1，因此代表了出色的疾病模型。我们假设tralpha1pv/+小鼠可用于预测人类THRA突变的骨骼结局，并确定用T4的超生理剂量延长治疗是否可以改善骨骼异常。成年雌性tralpha1pv/+小鼠的身材矮小，骨形态异常异常，但尽管骨骼质量很高，但骨强度正常。尽管T4治疗抑制了TSH分泌，但对骨骼成熟，线性生长或骨矿化没有影响，因此表现出对甲状腺激素的深刻耐药性。尽管如此，长期T4治疗异常增加了骨骼刚度和强度，这表明长期存在有害后果的可能性。我们的研究表明，Tralpha1在发展中和成人骨骼中具有重要作用，并预测患有不同THRA突变的患者将对T4治疗的反应可变，这取决于因果关系的严重程度。