PHYSIOLOGICAL ROLE OF THYROXINE BINDING PROTEINS

甲状腺素结合蛋白的生理作用

• 批准号: 6024376
• 负责人: PHILIP REED LARSEN
• 金额: $ 7.8万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-10 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6024376
• 关键词: enzyme mechanism; hormone metabolism; hormone regulation /control mechanism; human tissue; iodination; laboratory rat; language translation; northern blottings; posttranslational modifications; protein structure function; thyroid hormone binding protein; thyrotropin; thyroxine; triiodothyronine

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.

本申请旨在继续研究甲状腺素（T4）激活 这是该基金的第27个年头。 甲状腺的第一步 激素作用是T4的5 ′脱碘形成活性激素， 3，5，3 '-三碘甲状腺原氨酸（T3）。 最近的进展导致了克隆 2型碘甲状腺原氨酸脱碘酶cDNA（D2）的Km值较低（1 × 10-9 M）， 对丙硫氧嘧啶不敏感的硒代脱碘酶， 反应 新的信息表明， 这种酶在人类和大鼠之间的表达差异。 这些包括D2 mRNA在骨骼肌，心肌， 甲状腺组织，但在这些组织中很少或没有表达 在老鼠。 这表明，D2在 人类血浆T3的产生比我们以前认为的要多， 我们使用老鼠作为人类甲状腺激素代谢的模型。 D2 mRNA在人心肌中的存在表明， 像大脑和垂体一样，可能对血浆T4产生反应， 由于组织内局部T4转化为T3而导致的血浆T3。 因此，在本发明中， 这两种激素都可能影响心脏的甲状腺状态， 下丘脑-垂体轴 我们建议使用分子生物学技术来评估 人dio 2基因的转录调控，Ds的控制 mRNA翻译和D2活性的翻译后调节 由它的基质。 将在至关重要的方面进行修改 D2分子中的氨基酸来分析T4的机制 通过D2脱碘。 我们将探讨重要的氨基酸的作用机制， 酸的D2分子，以分析T4脱碘的机制， D2. 我们将探讨D2表达的机制和意义， 并将其与1型 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的反馈调节。 的 从这些研究中获得的信息对于理解 T4激活的最大可能性 这与人类疾病有关， 左旋甲状腺素用于治疗200多万 甲状腺功能减退的人，大多数是女性，仅在美国。 此外，委员会认为， D2的代偿性变化似乎是主要机制， 超过2.5亿人生活在碘下， 有缺陷的条件适应这种情况。