Is thyroxine more than a prohormone?

甲状腺素不仅仅是一种激素原吗？

• 批准号: 8283032
• 负责人: VALERIE Anne GALTON
• 金额: $ 20.03万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8283032
• 关键词: Accounting; Affect; Animals; Ataxia; Binding; Brain; Cells; Cerebrospinal Fluid; Cessation of life; Defect; Development; Enzymes; Exhibits; Exposure to; Female; Fetus; Gene Expression; Genes; Genomics; Growth; Hand; Hormone Responsive; Hormones; Human; Human Development; Hypothyroidism; Impairment; Indium; Iodide Peroxidase; Knock-out; Lead; Learning; Life; Ligands; Locomotion; Mediating; Mediator of activation protein; Memory; Mental Retardation; Modeling; Mouse Strains; Mus; Neonatal; Neurologic; Nuclear; Organ; Outcome; Perinatal; Phenotype; Physiological; Play; Positioning Attribute; Pregnancy; Process; Proteins; Rattus; Rodent; Role; Serum; Source; Testing; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Thyroxine; Time; Tissues; Transgenic Mice; Triiodothyronine; Wild Type Mouse; deafness; fetal; hormone deficiency; in vivo; iodothyronine deiodinase type I; male; mouse model; neurobehavioral; novel; postnatal; prohormone; pup; receptor; relating to nervous system; type 2 deiodinase (D2)

DESCRIPTION (provided by applicant): Thyroxine (T4), the principal circulating thyroid hormone (TH), is widely believed to be a prohormone that must be converted by the 5'-deiodinases (D1 and D2) to 3,5,3'-triiodothyronine (T3). T3 in turn binds to nuclear TH receptors (TRs) to mediate the genomic effects of this class of hormones. THs modulate numerous processes in almost every tissue in the body throughout life, and have long been known to play an essential role in brain development. TH deficiency in humans during the fetal and neonatal period results in irreversible developmental abnormalities including mental retardation, deafness and ataxia. Analogous impairments result from perinatal hypothyroidism in rodents. While the differential expression of TRs in the developing brain is a key element in determining the extent of TH action, the availability of the appropriate amount of their ligand is equally important. In te developing brain TH action is thought to be mediated predominantly, if not exclusively, by T3, with the majority of this ligand generated within the cells of this organ from T4 by the D2. However, this model cannot account for several recent findings. First, mice deficient in the D2 (the D2KO and D1/D2KO) and therefore totally dependent on the serum as the source of T3 in neural tissues, fail to show the severe neurobehavioral phenotype expected if D2 were the critical source of brain T3 during development. Second, a mouse deficient in the MCT8, a protein that preferentially transports T3 from serum into the brain, also demonstrates minimal neurological abnormalities. It is notable that in both these transgenic mouse strains the brain T3 content during the developmental period is reduced 40-50%, a reduction comparable to the level seen in highly compromised hypothyroid mice. Third, our preliminary observations indicate that a mouse deficient in both 5'- deiodinases and the MCT8 (the D1/D2/MCT8KO) also fails to manifest the severe defects in locomotion, learning and memory seen in the hypothyroid mouse, despite a brain T3 content significantly less than that observed in the latter condition. However, compared with WT mice, the serum and brain T4 contents are elevated in the D1/D2KO and D1/D2/MCT8KO mice and are substantial in the MCT8KO mouse. In sharp contrast, the T4 level is exceedingly low in the hypothyroid mouse, raising the possibility that T4 is directly effecting brain development. These observations lead us to hypothesize that T4 per se has intrinsic physiological activity in the brain that contributes significantly to the coordinated effcts of TH during development. We plan to test this hypothesis using our newly created D1/D2KO/Pax8-/- mouse, which can neither synthesize TH, nor convert administered T4 to T3. This unique model will allow for the first time a determination of the independent effects of T4 and T3 during development in vivo. These findings may result in a paradigmatic shift in our understanding of TH action in general and the importance of maternal T4 during pregnancy in particular. PUBLIC HEALTH RELEVANCE: Thyroxine (T4), the principal circulating thyroid hormone (TH), is widely believed to be a prohormone that must be converted by the 5'-deiodinases to 3,5,3'-triiodothyronine (T3) in order to exert a physiological effect. However, recent findings in our deiodinase-deficient animals have led us to hypothesize that T4 per se, in addition to being a prohormone, has intrinsic physiological activity. We plan to test this hypothesis using our newly created D1/D2KO/Pax8-/- mouse, which can neither synthesize TH, nor convert administered T4 to T3. This unique model will allow for the first time a determination of the independent effects of T4 and T3 during development in vivo. These findings may result in a paradigmatic shift in our understanding of TH action in general and the importance of maternal T4 during pregnancy in particular.

描述(申请人提供)：甲状腺激素(T4)，主要的循环甲状腺激素(TH)，被广泛认为是一种前激素，必须由5‘-脱碘酶(D1和D2)转化为3，5，3’-三碘甲状腺原氨酸(T3)。T3反过来与核TH受体(TRs)结合，以介导这类激素的基因组效应。THs在一生中调节着身体几乎每一个组织中的许多过程，长期以来一直被认为在大脑发育中扮演着重要的角色。人类在胎儿和新生儿期缺乏TH会导致不可逆转的发育异常，包括智力低下、耳聋和共济失调。类似的损害是由啮齿类动物的围产期甲状腺功能减退引起的。虽然Trs在发育中的大脑中的差异表达是决定TH作用程度的关键因素，但其适当数量的配体的可用性也同样重要。在TE发育的大脑中，TH的作用被认为是主要的，如果不是唯一的，由T3介导，大部分这种配体从T4开始由D2在这个器官的细胞内产生。然而，这个模型不能解释最近的几个发现。首先，缺乏D2(D2KO和D1/D2KO)的小鼠，因此在神经组织中完全依赖血清作为T3的来源，无法表现出如果D2是发育过程中脑T3的关键来源所期望的严重神经行为表型。其次，缺乏MCT8的小鼠也表现出轻微的神经异常。MCT8是一种优先将T3从血清输送到大脑的蛋白质。值得注意的是，在这两个转基因小鼠品系中，发育期大脑T3含量下降了40%-50%，与高度受损的甲状腺功能低下小鼠的水平相当。第三，我们的初步观察表明，同时缺乏5‘-脱碘酶和MCT8的小鼠(D1/D2/MCT8KO)也没有表现出甲状腺功能低下小鼠在运动、学习和记忆方面的严重缺陷，尽管脑中T3含量显著低于后一种情况。但与WT小鼠相比，D_1/D_2KO和D_1/D_2/MCT8KO小鼠的血清和脑组织T4含量均升高，而M_(CT8KO)小鼠的T_4含量较高。与之形成鲜明对比的是，甲状腺功能低下的小鼠体内T4水平极低，这增加了T4直接影响大脑发育的可能性。这些观察结果使我们假设T4本身在大脑中具有内在的生理活动，这对TH在发育过程中的协调作用有很大贡献。我们计划用我们新创造的D1/D2KO/Pax8-/-小鼠来验证这一假设，它既不能合成TH，也不能将T4转化为T3。这一独特的模型将首次确定T4和T3在体内发育过程中的独立作用。这些发现可能会导致我们对TH一般行为的理解的典型性转变，特别是在怀孕期间母体T4的重要性。 公共卫生相关性：甲状腺激素(T4)是主要的循环甲状腺激素(TH)，人们普遍认为它是一种前激素，必须由5‘-脱碘酶转化为3，5，3’-三碘甲状腺原氨酸(T3)才能发挥生理作用。然而，最近在我们的脱碘酶缺乏的动物中的发现使我们假设T4本身除了是一种激素原外，还具有内在的生理活性。我们计划用我们新创造的D1/D2KO/Pax8-/-小鼠来验证这一假设，它既不能合成TH，也不能将T4转化为T3。这一独特的模型将首次确定T4和T3在体内发育过程中的独立作用。这些发现可能会导致我们对TH一般行为的理解的典型性转变，特别是在怀孕期间母体T4的重要性。