REGULATION OF THYROID FUNCTION--T4 AND T3 KINETICS

甲状腺激素对身体健康至关重要， 对胎儿和新生儿大脑发育很重要。 它们被隐藏在 两种形式，（T4）和3，5，3 '-三碘甲腺原氨酸（T3）。 T3调节 许多基因的转录。 相比之下，T4基本上不活动， 除非转化为T3。 这一过程被称为外周 转化由至少两种不同的酶控制，I型和 II型5 ′-脱碘酶（5 ′ D-I和5 ′ D-II）。原发性甲状腺功能障碍 是甲状腺功能不全和甲状腺激素过多的主要原因。它 现在很明显，T4的外周脱碘产生T3起到了 不仅在调节T3的总体供应方面， 选择性地调节不同器官内的T3浓度。 两 最近的发现使人们重新关注甲状腺外的 调节甲状腺激素对外周血的可用性的事件 组织中 首先，5 'D-I，被认为是负责 外周转化从分泌的T4产生血浆T3，是一种 硒需要酶。 第二，甲状腺素运载蛋白（TTR）在 在脉络丛中合成的脑脊髓液构成了 T4的运输系统，而不是T3，到大脑。 的 本补助金中提出的研究将确定5 'D-I的重要性， 硒蛋白对血浆碘甲腺原氨酸的产生和清除， 特别是T3，并探讨硒缺乏对 新生儿甲状腺稳态与甲状腺激素依赖性脑 成熟 我们还将试图确定的贡献， 新T3合成和甲状腺T4的5 'D-脱碘以产生T3， 甲状腺分泌T3的总量。 这些研究将使用硒 缺乏，这损害了5 'D-I活性的肝脏和肾脏，但不 甲状腺和PTU类似物，不影响甲状腺激素 合成，但确实抑制肝、肾和甲状腺中的5 'D-I活性。 还将进行研究，以确定脑脊髓的作用， 液体TTR在甲状腺激素依赖性转运和调节中的作用 大脑中的过程。

Thyroid hormones are essential for good health and are also critically important for fetal and neonatal brain development. They are secreted in two forms, (T4) and 3,5,3'-triiodothyronine (T3). T3 regulates the transcription of many genes. T4, in contrast, is essentially inactive for genomic processes unless converted to T3. This process, termed peripheral conversion, is controlled by at least two distinct enzymes, the Type I and the Type II 5'-deiodinases (5'D-I and 5'D-II). Primary thyroid dysfunction is the major cause of thyroid insufficiency and thyroid hormone excess. it is now apparent that peripheral deiodination of T4 to generate T3 plays a major role not only in regulating the overall supply of T3 but also in selectively modulating T3 concentrations within distinct Organs. Two recent discoveries have focused renewed attention on the extrathyroidal events regulating the availability of thyroid hormones to peripheral tissues. First, 5'D-I, considered to be the major enzyme responsible for peripheral conversion to generate plasma T3 from secreted T4, is a selenium requiring enzyme. Second, transthyretin (TTR) in the cerebrospinal fluid, synthesized in the choroid plexus, constitutes a specialized system for transport of T4, but not T3, to the brain. The studies proposed in this grant will define the importance of the 5'D-I selenoprotein to the generation and clearance of plasma iodothyronines, particularly T3, and explore the consequences of selenium deficiency on neonatal thyroid homeostasis and thyroid hormone dependent brain maturation. We will also attempt to determine the contributions of de novo T3 synthesis and thyroid 5'D-deiodination of T4 to generate T3 to the overall secretion of T3 from the thyroid. These studies will use selenium deficiency, which impairs 5'D-I activity in liver and kidney but not in the thyroid, and an analog of PTU, which does not affect thyroid hormone synthesis but does inhibit 5'D-I activity in liver, kidney and thyroid. Studies will also be performed to establish the role of cerebrospinal fluid TTR in the transport and regulation of thyroid hormone dependent processes in the brain.