PHYSIOLOGICAL ROLE OF THYROXINE-BINDING PROTEINS

这项应用是为了继续研究甲状腺激素(T4)的激活 根据一项赠款，目前已进入第27个年头。甲状腺的第一步 激素作用是T4的5‘脱碘形成活性荷尔蒙， 3，5，3‘-三碘甲腺原氨酸(T3)。最近的进展导致了克隆 型碘甲腺原氨酸脱碘酶基因(D2)中，低Km(1×10-9M)， 丙基硫氧嘧啶不敏感的硒脱碘酶催化这一过程 反应。新的信息表明，有重要的 这种酶在人和大鼠之间的表达差异。 其中包括D2mRNA在骨骼肌、心肌和 人的甲状腺组织，但在这些组织中很少或没有表达 在老鼠身上。这表明D2在人类免疫系统中起着更为重要的作用 人类血浆中T3的产生比我们之前认为的要好 我们用大鼠作为人类甲状腺激素代谢的模型。 人类心肌中D2mRNA的存在表明，心脏， 就像大脑和脑下垂体一样，可能对血浆T4产生独立的反应 由于组织内局部T4向T3的转化，导致血浆T3升高。因此， 这两种荷尔蒙也可能有助于心脏的甲状腺状态。 作为下丘脑-脑垂体轴。 我们建议使用分子生物学技术来评估 人类dio2基因转录调控与DS的调控 信使核糖核酸翻译与D2活性的翻译后调节 通过它的底物。将在极其重要的情况下进行修改 用D2分子中的氨基酸分析T4的作用机制 D2脱碘。我们将探索重要氨基的作用机制 D2分子中的酸来分析T4脱臭的机制 D2。我们将探索D2表达的机制和意义 并将其与1型进行比较 碘甲腺原氨酸脱碘酶也存在于该组织中。最后，我们将 评估D2在中枢神经系统中的关键作用 传感器在甲状腺功能反馈调节中的作用。这个 来自这些研究的信息对于理解生理学至关重要。 T4在人类体内的激活。这与人类疾病有关，因为 左旋甲状腺素用于治疗200多万人 甲状腺功能减退者，主要是女性，仅在美国。此外， D2的代偿性变化似乎是主要的机制 通过它，生活在碘下的2.5亿人- 不足的条件与这种情况相适应。

This application is to continue the study of thyroxine (T4) activation under a grant which is now in its 27th year. The first step in thyroid hormone action is the 5' deiodination of T4 to form the active hormone, 3,5,3'-triiodothyronine (T3). Recent progress has led to the cloning of the type 2 iodothyronine deiodinase cDNA (D2), a low Km (1 x 10-9 M), propylthiouracil-insensitive selenodeiodinase which catalyzes this reaction. New information indicates that there are important differences in the expression of this enzyme between humans and rats. These include the expression of D2 mRNA in skeletal, cardiac muscle, and thyroid tissue in humans but little or no expression in these tissues in the rat. This indicates that D2 has a much more important role in the production of plasma T3 in humans than we had previously thought due to our use of the rat as a model for human thyroid hormone metabolism. The presence of D2 mRNA in human myocardium suggests that the heart, like the brain and pituitary, may respond to plasma T4 independent of the plasma T3 due to local T4 to T3 conversion within the tissue. Thus, both hormones may contribute to the thyroid status of the heart, as well as the hypothalamic-pituitary axis. We propose to use molecular biological techniques to evaluate the transcriptional regulation of the human dio2 gene, the control of Ds mRNA translation, and the post-translational regulation of D2 activity by its substrates. Modifications will be made in critically important amino acids in the D2 molecule to analyze the mechanism of T4 deiodination by D2. We will explore the mechanism for important amino acids in the D2 molecule to analyze the mechanism of T4 deodination by D2. We will explore the mechanism for and significance of D2 expression in the human thyroid and compare this with that of the type 1 iodothyronine deiodinase also present in this tissue. Lastly, we will evaluate the role of D2 in the central nervous system as the critical transducer in the feedback regulation of thyroid function. The information from these studies is vital to understanding the physiology of T4 activation in humans. This is relevant for human disease since levothyroxine is used in the treatment of the over two million hypothyroid persons, mostly women, in the U.S.A. alone. Furthermore, it seems likely that compensatory changes in D2 are the major mechanism by which the more than 250 million individuals living under iodine- deficient conditions adapt to this circumstance.