PHYSIOLOGICAL ROLE OF THYROXINE-BINDING PROTEINS

甲状腺素结合蛋白的生理作用

• 批准号: 7555401
• 负责人: PHILIP REED LARSEN
• 金额: $ 3.94万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555401
• 关键词: 3-monoiodothyronine; Address; Adult; Affect; Amino Acids; Binding; Biochemical; Biological; Blood Circulation; Brazil; Catalysis; Cell Nucleus; Cells; Confocal Microscopy; Development; Endocrinology; Enzymes; Excision; Extracellular Space; Family; Fasting; Gene Expression; Grant; Heart; Hemangioma; Homodimerization; Hormones; Human; Hypothalamic structure; Hypothyroidism; In Vitro; Individual; Infant; Integral Membrane Protein; Investigation; Iodide Peroxidase; Iodine; Iodothyronine Deiodinase; Kidney; Life; Light; Liver; Microscopic; Modification; Molecular; Monitor; Myocardium; Nuclear; Oxidoreductase; Pathway interactions; Pattern; Physiological; Physiology; Plasma; Principal Investigator; Production; Property; Proteins; Recombinants; Regulation; Relative (related person); Repression; Rodent; Role; Source; System; Techniques; Thyroid Gland; Thyroid Hormones; Thyroxine; Thyroxine-Binding Proteins; Time; Tissues; United States National Institutes of Health; cofactor; deiodination; extracellular; in vitro Model; in vivo; iodine deficiency syndrome; medical schools; member; overexpression; parent grant; pituitary thyroid axis; programs; prohormone; response; simulation; uptake

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.

这项合作研究将在巴西内分泌科，医学院， 南里奥格兰德联邦大学，作为NIH资助#RO 1 DK-36256的扩展， 在生理条件下对碘甲腺原氨酸脱碘酶的功能进行了深入研究， 人类的病理生理环境。1、2和3型脱碘酶（D1、D2和D3） 构成氧化还原酶家族，其催化碘从外层（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 以组织特异性方式在细胞内甲状腺状态中，而不影响全身甲状腺激素 程度.在这些研究中，我们将探索在完整细胞中催化的机制， 硒代脱碘酶家族成员，D3。D3酶催化T4的失活， T3及其过度表达，如发生在大血管瘤中，会导致严重的甲状腺功能减退， 婴儿和成人。D3活性增加，引起局部甲状腺功能减退，也可能是重要的， 人类对疾病或禁食以保存能量的适应性反应。此外，增加 在衰竭的心脏中已经证实了D3活性，表明局部细胞内TS的减少 可能导致心肌甲状腺功能减退。我们的共聚焦显微镜研究 预测D3的活性催化中心在细胞外。我们将确定甲状腺激素 D3的失活发生在细胞外空间，以及催化作用是否可以通过以下方式改变： 通过不渗透的探针或通过阻断正常的细胞内酶的共价修饰， D3的循环本文提出的研究将阐明这种脱碘酶的功能， 对我们理解控制甲状腺激素水平的因素有重要意义， 健康和生病的人。

项目成果

Type 2 iodothyronine deiodinase is highly expressed in medullary thyroid carcinoma.

2 型碘甲状腺原氨酸脱碘酶在甲状腺髓样癌中高表达。

• DOI: 10.1016/j.mce.2008.04.009
• 发表时间: 2008
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Meyer,ErikaLSouza;Goemann,IuriM;Dora,JoséMiguel;Wagner,MarciaS;Maia,AnaLuiza
• 通讯作者: Maia,AnaLuiza

The role of thyroid hormone in testicular development and function.

• DOI: 10.1677/joe-08-0218
• 发表时间: 2008-12
• 期刊: The Journal of endocrinology
• 作者: Wagner MS;Wajner SM;Maia AL
• 通讯作者: Maia AL