PHYSIOLOGICAL ROLE OF THYROXINE-BINDING PROTEINS

甲状腺素结合蛋白的生理作用

• 批准号: 6999753
• 负责人: PHILIP REED LARSEN
• 金额: $ 39.7万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999753
• 关键词: PHYSIOLOGICAL; ROLE; THYROXINE; BINDING; PROTEINS

DESCRIPTION (provided by applicant): The first step in the activation of the prohormone, thyroxine (T4), is its 5' monodeiodination to T3, catalyzed by the types 1 and 2 iodothyronine deiodinase. Type 3 deiodinase (03) catalyzed removal of an inner ring iodine inactivating T4 or T3. These three enzymes have two common features; they are integral membrane proteins and all have the rare amino acid selenocysteine in their active center to serve as the iodine acceptor. They confer two general advantages to the regulation of thyroid hormone action. First, during embryological development, activation and inactivation of thyroid hormone is programmed to occur at specific times in specific cells to allow either induction or repression of thyroid hormone-dependent gene expression. Second, throughout life, the important role of D2 in the hypothalamic-pituitary-thyroid axis permits the terrestrial vertebrate to adapt to iodine deficiency by monitoring the concentration of T4 in the circulation. This permits increases in TRH and TSH secretion, long before the concentrations of the active hormone, T3, decrease. In humans, it has long been assumed that D1, present in high concentrations in the liver and kidney, is the major source of circulating T3. More recent analyses of D2 expression patterns together with older in vivo results suggest that this is not the case and that most plasma T3 in humans probably derives from the activation of T4 by D2. This enzyme is widely expressed in humans, but not in rodents. The present proposal will focus on 3 aspects of the molecular physiology of the deiodinases. Specific Aim I will analyze the causes of the unique topology and subcellular localizations of D1, 02 and D3 in the cell using confocal microscopy and cell biological techniques. Specific Aim II will employ cells expressing endogenous or recombinant D1 and 02 to understand why D2 is the major enzyme catalyzing extrathyroidal T3 production in humans. We also will determine why the T3 produced by D2-catalyzed T4 5'-deiodination enters the nucleus whereas that generated by D1 does not. Specific Aim Ill will address the issue of the active form of the three enzymes. Are they homodimers or do they interact with other proteins? We will also analyze the functional effects of this interaction. These studies will thus address the basic mechanisms by which thyroid hormone activation and inactivation are regulated in both normal and pathological states.

描述（由申请人提供）：激素原甲状腺素（T4）活化的第一步是由1型和2型碘甲腺原氨酸脱碘酶催化其5'单脱碘为T3。3型脱碘酶（03）催化去除使T4或T3失活的内环碘。这三种酶有两个共同的特点：它们都是完整的膜蛋白，并且在它们的活性中心都有稀有的氨基酸硒代半胱氨酸作为碘受体。它们赋予甲状腺激素作用的调节两个一般优点。首先，在胚胎发育期间，甲状腺激素的激活和失活被编程为在特定细胞中的特定时间发生，以允许诱导或抑制甲状腺激素依赖性基因表达。其次，在整个生命过程中，D2在下丘脑-垂体-甲状腺轴中的重要作用允许陆生脊椎动物通过监测循环中T4的浓度来适应碘缺乏。这使得TRH和TSH分泌增加，早在活性激素T3的浓度降低之前。在人类中，长期以来一直认为，在肝脏和肾脏中以高浓度存在的D1是循环T3的主要来源。最近对D2表达模式的分析以及较早的体内结果表明，情况并非如此，人体中大多数血浆T3可能与T2表达模式有关。 源自D2对T4的激活。这种酶在人类中广泛表达，但在啮齿动物中不表达。本文主要从三个方面对脱碘酶的分子生理学进行了研究。具体目的我将使用共聚焦显微镜和细胞生物学技术分析D1，02和D3在细胞中的独特拓扑结构和亚细胞定位的原因。具体目标II将采用表达内源性或重组D1和02的细胞，以了解为什么D2是催化人类甲状腺外T3产生的主要酶。我们还将确定为什么由D2催化的T4 5 '-脱碘产生的T3进入细胞核，而由D1产生的T3却没有。具体目标III将解决这三种酶的活性形式的问题。它们是同源二聚体还是与其他蛋白质相互作用？我们还将分析这种相互作用的功能效应。因此，这些研究将解决甲状腺激素的激活和失活的调节在正常和病理状态下的基本机制。