Analysis of mice mutants deficient in the thyroid hormone transporter MCT8

甲状腺激素转运蛋白 MCT8 缺陷小鼠突变体分析

• 批准号: 117145524
• 负责人: Professorin Dr. Heike Heuer
• 金额: --
• 依托单位: Klinik für Endokrinologie und Stoffwechselerkrankungen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/117145524?language=en
• 关键词: Analysis; mice; mutants; deficient; thyroid

Thyroid hormone actions and metabolism are intracellular events that require the transport of iodothyronines across the plasma membrane. This process is facilitated by thyroid hormone transporters of which the monocarboxylate transporter 8 (MCT8) has been most intensively analyzed. In humans, inactivating mutations in the X-linked MCT8 gene are associated with a severe form of psychomotor retardation in combination with abnormal serum thyroid hormone parameters. Based on these findings it has been speculated that absence of MCT8 results in insufficient neuronal thyroid hormone supply during critical stages of development. We recently provided a first description of MCT8 deficient mice that despite the absence of overt neurological symptoms exhibit the same unusual thyroid hormone parameters as found in patients carrying MCT8 mutations. Here, we aim to unravel the pathogenic mechanisms that lead to the altered serum thyroid state. For this purpose, we will especially focus on the analysis of the thyroid gland and kidney as putative tissues that contribute significantly to the generation of the abnormal thyroid hormone levels. Furthermore, we will analyze in great detail the central resistance to thyroid hormone within the hypothalamus-pituitary axis. By defining the mechanisms that cause the abnormal serum thyroid parameters in MCT8 null mice we hope our studies will provide also an insight to ameliorate the devastating conditions of patients with MCT8 mutations.

甲状腺激素的作用和代谢是细胞内的事件，需要碘甲状腺原氨酸跨质膜运输。这一过程由甲状腺激素转运蛋白促进，其中单羧酸转运蛋白8（MCT 8）已被最深入地分析。在人类中，X连锁MCT 8基因的失活突变与严重形式的精神发育迟滞以及异常的血清甲状腺激素参数相关。基于这些发现，推测在发育的关键阶段，MCT 8的缺乏导致神经元甲状腺激素供应不足。我们最近首次描述了MCT 8缺陷小鼠，尽管没有明显的神经系统症状，但其甲状腺激素参数与携带MCT 8突变的患者相同。在这里，我们的目标是解开致病机制，导致血清甲状腺状态的改变。为此，我们将特别关注对甲状腺和肾脏的分析，因为甲状腺和肾脏被认为是导致甲状腺激素水平异常的重要组织。此外，我们将详细分析下丘脑-垂体轴内对甲状腺激素的中枢抵抗。通过定义导致MCT 8缺失小鼠血清甲状腺参数异常的机制，我们希望我们的研究也能为改善MCT 8突变患者的破坏性疾病提供见解。