Analysis of mice mutants deficient in the thyroid hormone transporter MCT8

甲状腺激素的作用和代谢是细胞内的事件，需要通过质膜运输碘甲状腺原氨酸。这一过程是由甲状腺激素转运蛋白促进的，其中单羧酸转运蛋白8(MCT8)是分析最深入的。在人类中，X连锁MCT8基因的失活突变与严重的精神运动发育迟缓和血清甲状腺激素参数异常有关。根据这些发现，推测MCT8的缺失导致发育关键阶段的神经元甲状腺激素供应不足。我们最近首次描述了MCT8缺陷小鼠，尽管没有明显的神经症状，但表现出与携带MCT8突变的患者相同的异常甲状腺激素参数。在这里，我们旨在揭示导致血清甲状腺状态改变的致病机制。为此，我们将特别关注甲状腺和肾脏的分析，它们是导致甲状腺激素水平异常的重要原因。此外，我们还将详细分析下丘脑-垂体轴对甲状腺激素的中枢抵抗。通过确定导致MCT8基因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将为改善MCT8突变患者的破坏性条件提供见解。

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.