REGULATION OF THYROID FUNCTION--T4 AND T3 KINETICS

甲状腺激素对健康是必不可少的，也是至关重要的 对胎儿和新生儿的大脑发育很重要。它们被秘密地藏在 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基本上不活跃于 基因组过程，除非转化为T3。这一过程称为外周 转化，至少由两种不同的酶控制，类型I和 II型5‘-脱碘酶(5’D-I和5‘D-II)。原发性甲状腺功能障碍 是导致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的外周去碘作用产生了T3 不仅在调节T3的总体供应方面发挥主要作用，而且在 选择性地调节不同器官内的T3浓度。二 最近的发现使人们重新关注甲状腺外激素。 调节外周甲状腺激素可利用性的事件 纸巾。首先，5‘D-I，被认为是负责 从分泌的T4产生血浆T3的外周转换是一种 需要酶的硒。第二，甲状腺激素受体(TtR) 在脉络丛中合成的脑脊液构成了 将T4而不是T3输送到大脑的专门系统。这个 这项拨款中提议的研究将确定5‘D-I的重要性 硒蛋白与血浆碘甲状腺原氨酸的产生和清除有关， 特别是T3，并探讨缺硒对机体的影响 新生儿甲状腺稳态与甲状腺激素依赖脑 成熟。我们还将尝试确定De Novo T_3合成和甲状腺5‘-D-脱碘T_4生成T_3 甲状腺分泌的总T3。这些研究将使用硒 缺乏，损害肝脏和肾脏的5‘D-I活性，但不影响 甲状腺，以及PTU的类似物，不影响甲状腺激素 但对肝脏、肾脏和甲状腺的5‘D-I活性有抑制作用。 还将进行研究，以确定脑脊液的作用 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.