Thyroid Hormone Receptor Isoform-Specific Actions

甲状腺激素受体亚型特异性作用

• 批准号: 7017825
• 负责人: GREGORY A BRENT
• 金额: $ 28.3万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017825
• 关键词: adipose tissue; biological signal transduction; body composition; gene mutation; genetic models; genetic regulation; genetically modified animals; heart function; hormone receptor; hormone regulation /control mechanism; insulin sensitivity /resistance; laboratory mouse; liver; metabolism; peroxisome proliferator activated receptor; protein isoforms; receptor expression; thermogenesis; thyroid function; thyroid hormones

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.

描述（由申请人提供）：甲状腺激素对于调节一系列过程至关重要，包括神经发育，骨骼发育，体细胞生长，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，局部和全身性激活以及脱碘二世酶酶对甲状腺激素的失活以及甲状腺激素受体（TR）在目标组织中的差异表达来实现的。多种动物模型以及甲状腺激素作用不足的人类的观察结果已经确定了甲状腺激素受体同工型的特定作用。甲状腺激素的许多作用都可以由Tralpha或beta介导，但其他动作对于一种TRE同工型非常具体。在大脑，发育中的耳朵，视网膜，垂体，心脏，肝脏和棕色脂肪组织（BAT）中已经确定了特异性作用。该建议将利用遗传模型和药理学剂来识别和研究代谢，适应性生热和心脏功能中TR同工型特异性作用的机制。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，肝脏和心脏的作用的整合。我们的Tralphap398H突变小鼠在肾上腺素能信号中的重要性证明了内脏肥胖，胰岛素抵抗，脂肪肝，缺陷的适应性热和有明显的儿茶酚胺介导的脂肪分解的表型。这项研究的具体目的包括： （1）表征tralpha和beta在WAT和BAT中代谢调节中的作用，重点是Tralpha在介导儿茶酚胺敏感性中的作用，（2）表征Tralphap398h突变小鼠中代谢表型的表征。血清脂蛋白谱，肝基因表达，体内脂肪组成，胰岛素敏感性以及对甲状腺状态变化的反应，性腺状态以及pParalpha和pparalpha和Gamma激动剂的治疗，（3）表征Tralpha在心脏功能和基因表达中的作用，包括对运动的动态影响，包括对运动的动态影响，以构成属于果冻的动态影响，以降级（降级）（降级）（降低了果肉的动态影响） Tralpha特异性基因调节的机制，尤其是Tralpha显性阴性突变对基因调节的影响。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，这对理解潜在机制并开发了针对肥胖，胰岛素抵抗和心血管疾病的新型治疗方法的影响。