PHYSIOLOGICAL ROLE OF THYROXINE-BINDING PROTEINS

这项合作研究将在巴西哥伦比亚大学医学院内分泌科进行 南里奥格兰德河联邦大学，作为国立卫生研究院#RO1 DK-36256号拨款的延伸 生理和生理条件下碘甲腺原氨酸脱碘酶功能的研究进展 人类的病理生理环境。脱碘酶1、2和3型(d1、d2和d3) 组成一个氧化还原酶家族，催化从外部(d1和 D2，激活)或内环(D1和D3，失活)的甲状腺激素。脱碘 途径是甲状腺激素激活和失活的关键步骤，允许快速变化。 以组织特有的方式处于细胞内甲状腺状态，而不影响全身甲状腺激素 级别。在这些研究中，我们将通过第三个步骤来探索完整细胞的催化机制 硒脱碘酶家族的成员，D3。D3酶催化T4失活和 T3及其过度表达，如在大血管瘤中所发生的那样，导致严重的甲状腺功能减退 婴儿和成年人。D3活性的增加，导致局部甲状腺功能减退，可能也是 人类对疾病或禁食以保存能量的适应性反应。此外，增加了 D3活性已在衰竭的心脏中被证实，表明局部细胞内TS减少 可能导致心肌中的甲状腺功能减退。我们的共焦显微镜研究 预测D3的活性催化中心在胞外。我们将确定甲状腺激素是否 D3的失活发生在细胞外空间，以及催化是否可以被其中之一改变 用不必要的探针或通过封闭正常的细胞内对酶进行共价修饰 D3的骑行。这里提出的研究将阐明这种脱碘酶的功能，并将 对于我们理解控制甲状腺激素水平的因素具有重要的意义 健康的和患病的个体。

This collaborative study will be performed in Brazil at the Endocrinology Division, Medical School of the Universidade Federal do Rio Grande do Sul, as an extension of NIH grant # RO1 DK-36256 to extend studies on the function of the iodothyronine deiodinases under physiological and pathophysiological circumstances in humans. The types 1, 2, and 3 deiodinases (D1,D2, and D3) constitute a family of oxidoreductases that catalyze the removal of iodine from the outer (D1 and D2, activation) or inner ring (D1 and D3, inactivation) of the thyroid hormones. The deiodination pathway is a critical step in thyroid hormone activation and inactivation, allowing for rapid changes in intracellular thyroid status in a tissue-specific manner, without affecting systemic thyroid hormone levels. In these studies, we will explore the mechanism of catalysis in intact cells by the third member of the selenodeiodinase family, D3. The D3 enzyme catalyzes the inactivation of T4 and T3 and its overexpression, as occurs in large hemangiomas, causes severe hypothyroidism in infants and adults. Increases in D3 activity, causing local hypothyroidism, may also be important in the adaptive response of humans to illness or fasting to conserve energy. Furthermore, increased D3 activity has been demonstrated in failing hearts, indicating that reduction of local intracellularTS may contribute to a hypothyroid condition in the myocardium. Our confocal microscopic studies predict that the active catalytic center of D3 is extracellular. We will determine if thyroid hormone inactivation by D3 occurs in the extracellular space and whether catalysis can be altered by either covalent modification of the enzyme by impermeant probes or by blocking the normal intracellular cycling of D3. The studies proposed here will shed light on the function of this deiodinase and will have major implications for our understanding of factors controlling thyroid hormone levels in healthy and sick individuals.