Thyroid Hormone Receptor Isoform-Specific Actions

描述（由申请人提供）：甲状腺激素对调节一系列过程至关重要，包括神经发育、骨发育、躯体生长、心脏功能和代谢。甲状腺激素作用的调节是通过下丘脑-垂体-甲状腺轴对甲状腺激素产生的严格控制、脱碘酶对甲状腺激素的局部和全身激活和失活以及靶组织中甲状腺激素受体（TR）亚型的差异表达来实现的。各种动物模型和对甲状腺激素作用缺陷的人类的观察已经确定了甲状腺激素受体亚型的特定作用。甲状腺激素的许多作用可以由TR α或β介导，但其他作用对TR同种型非常特异。TR亚型特异性作用已在脑、发育中的耳、视网膜、脑垂体、心脏、肝脏和棕色脂肪组织（BAT）中鉴定。该提案将利用遗传模型和药理学试剂来识别和研究TR亚型在代谢、适应性产热和心脏功能中特异性作用的机制。拟议的研究将特别关注代谢控制中甲状腺介导的信号与白色脂肪组织（WAT）、BAT、肝脏和心脏中的作用的整合。我们的TRalphaP 398 H突变小鼠证明了TRalpha在肾上腺素能信号传导中的重要性，该小鼠具有内脏肥胖、胰岛素抵抗、脂肪肝、适应性产热缺陷和WAT中儿茶酚胺介导的脂解的显著缺陷的表型。本研究的具体目的包括：（1）研究TRalpha和β在WAT和BAT代谢调节中的作用，重点是TRalpha在介导儿茶酚胺敏感性中的作用;（2）研究TRalpha P398 H突变小鼠的代谢表型，包括：血清脂蛋白谱、肝脏基因表达、体脂组成、胰岛素敏感性和对甲状腺状态变化的反应，性腺状态和PPARalpha和gamma激动剂治疗，（3）表征TRalpha在心脏功能和基因表达中的作用，包括运动的动态效应和儿茶酚胺对心脏的短期和长期影响，（4）利用体外模型研究TRalpha -1的作用机制。特异性基因调控，特别是TRalpha显性负突变对基因调控的影响。这些研究的结果将为TR在代谢信号传导中的作用提供重要的见解，对理解潜在的机制和开发肥胖，胰岛素抵抗和心血管疾病的新治疗方法具有重要意义。

DESCRIPTION (provided by applicant): Thyroid hormone is essential for the regulation of a range of processes including neural development, bone development, somatic growth, cardiac function, and metabolism. The regulation of thyroid hormone action is accomplished through tight control of thyroid hormone production by the hypothalamic-pituitary-thyroid axis, local and systemic activation and inactivation of thyroid hormone by deiodinase enzymes, and differential expression of thyroid hormone receptor (TR) isoforms in target tissues. A variety of animal models, and observations from humans with deficits of thyroid hormone action, have identified specific roles for thyroid hormone receptor isoforms. Many actions of thyroid hormone can be mediated by either TRalpha or beta, but others are quite specific for one TR isoform. TR isoform-specific actions have been identified in the brain, developing ear, retina, pituitary, heart, liver, and in brown adipose tissue (BAT). This proposal will utilize genetic models and pharmacological agents to identify and study the mechanism of TR isoform-specific actions in metabolism, adaptive thermogenesis, and cardiac function. The proposed studies will especially focus on the integration of thyroid-mediated signals in metabolic control with actions in white adipose tissue (WAT), BAT, liver, and heart. The importance of TRalpha in adrenergic signaling is demonstrated by our TRalphaP398H mutant mouse, with the phenotype of visceral obesity, insulin resistance, fatty liver, defective adaptive thermogenesis, and a marked deficit of catecholamine-mediated lipolysis in WAT. The specific aims of this study include; (1) To characterize the role ofTRalpha and beta in metabolic regulation in WAT and BAT, focusing on the action of TRalpha in mediating catecholamine sensitivity, (2) To characterize the metabolic phenotype in TRalphaP398H mutant mice including; serum lipoprotein profile, hepatic gene expression, body fat composition, insulin sensitivity, and response to changes in thyroid status, gonadal status and with PPARalpha and gamma agonist treatment, (3) To characterize the role of TRalpha in cardiac function and gene expression, including dynamic effects of exercise and the short and long-term influence of catecholamines on the heart, (4) To utilize in vitro models to determine the mechanisms of TRalpha -specific gene regulation and especially the influence of the TRalpha dominant negative mutations on gene regulation. The results of these studies will provide important insights into the role of TR in metabolic signaling, with implications for understanding underlying mechanisms and developing novel treatments for obesity, insulin resistance, and cardiovascular disease.