Is thyroxine more than a prohormone?

甲状腺素不仅仅是一种激素原吗？

• 批准号: 8448119
• 负责人: VALERIE Anne GALTON
• 金额: $ 19.19万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448119
• 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.

描述（由申请人提供）：甲状腺素（T4）是主要的循环甲状腺激素（TH），被广泛认为是一种激素原，必须通过5 '-脱碘酶（D1和D2）转化为3，5，3'-三碘甲状腺原氨酸（T3）。T3又与核TH受体（TR）结合，以介导这类激素的基因组效应。TH在整个生命过程中调节身体几乎每个组织中的许多过程，并且长期以来一直被认为在大脑发育中发挥重要作用。人类在胎儿和新生儿时期的TH缺乏导致不可逆的发育异常，包括智力迟钝、耳聋和共济失调。啮齿类动物的围产期甲状腺功能减退也会导致类似的损伤。虽然TR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，但其配体的适当量的可用性同样重要。在发育中的脑中，TH作用被认为主要（如果不是唯一的话）由T3介导，其中该配体的大部分在该器官的细胞内由D2从T4产生。然而，这个模型不能解释最近的几个发现。首先，缺乏D2（D2 KO和D1/D2 KO）并因此完全依赖血清作为神经组织中T3来源的小鼠，未能显示出如果D2是发育期间脑T3的关键来源所预期的严重神经行为表型。其次，一只缺乏MCT 8的小鼠，也表现出最小的神经系统异常，MCT 8是一种优先将T3从血清转运到大脑的蛋白质。值得注意的是，在这两种转基因小鼠品系中，发育期间的脑T3含量降低了40- 50%，与在高度受损的甲状腺功能减退小鼠中观察到的水平相当。第三，我们的初步观察表明，5 '-脱碘酶和MCT 8缺陷的小鼠（D1/D2/MCT 8 KO）也没有表现出甲状腺功能减退小鼠中观察到的运动、学习和记忆的严重缺陷，尽管脑T3含量显著低于在后一种情况下观察到的。然而，与WT小鼠相比，在D1/D2 KO和D1/D2/MCT 8 KO小鼠中血清和脑T4含量升高，并且在MCT 8 KO小鼠中显著升高。与此形成鲜明对比的是，甲状腺功能减退小鼠的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性，其在发育过程中对TH的协调作用有显着贡献。我们计划使用我们新创建的D1/D2 KO/Pax 8-/-小鼠来测试这一假设，该小鼠既不能合成TH，也不能将施用的T4转化为T3。这种独特的模型将首次确定T4和T3在体内发育过程中的独立影响。这些发现可能会导致我们对TH作用的理解发生范式转变，特别是在怀孕期间母体T4的重要性。