The tissue-specific role of the murine thyroid hormone transporters Mct8 and Mct10

甲状腺激素(TH)的作用和代谢是细胞内的事件，需要TH跨质膜运输。这一过程是由转运蛋白促进的，其中单羧酸转运蛋白8(MCT8)被分析得最深入。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TH参数异常有关。我们最近提供了Mct8缺陷小鼠的详细描述，尽管没有明显的神经系统症状，但显示出与携带MCT8突变的患者相同的异常血清TH参数。由于TH谱的改变以及不同器官中TH运输的变化，Mct8 Ko小鼠表现出组织特异性TH过剩和缺乏的复杂表型，这阻碍了对Mct8组织特异性作用的分析。在这里，我们的目标是通过利用以细胞特异性方式表达cre-重组酶的条件Mct8小鼠突变体来揭示Mct8细胞特异性失活对组织动态平衡以及血清TH谱的影响。我们将特别研究肝、甲状腺和肾脏中Mct8细胞特异性失活的后果，因为这三个组织都受到Mct8缺乏症的很大影响，并被认为参与了血清TH水平异常的产生。此外，我们的目标是剖析Mct8在下丘脑中的细胞特异性功能，Mct8存在于神经元、毛细血管细胞和张力细胞中。我们进一步在我们的研究中包括了同样缺乏甲状腺激素转运蛋白Mct10的小鼠突变，因为我们使用传统的Mct8/Mct10缺乏的小鼠突变的分析表明，肾脏、肝脏和甲状腺中的两个TH转运蛋白具有协同作用。最重要的是，Mct10的失活导致Mct8缺乏症所特有的异常血清TH水平的部分正常化，通过使用条件小鼠突变体，我们旨在揭示其潜在的机制。综上所述，我们旨在阐明Mct8和Mct10在促进TH进入其靶组织中的意义，并进一步阐明导致Mct8缺陷小鼠血清甲状腺参数异常的机制。我们也希望我们的研究将为改善MCT8突变患者的破坏性条件提供一个见解。

Thyroid hormone (TH) actions and metabolism are intracellular events that require the transport of TH across the plasma membrane. This process is facilitated by TH 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 TH parameters. We recently provided a detailed description of Mct8 deficient mice that despite the absence of overt neurological symptoms exhibit the same unusual serum TH parameters as patients carrying MCT8 mutations. As a consequence of the altered TH profile as well as changes in TH transport in various organs, Mct8 ko mice exhibit a complex phenotype of tissue-specific TH excess and deprivation that impedes the analysis of the tissue-specific role of Mct8. Here, we aim to unravel the consequences of a cell-specific inactivation of Mct8 on tissue homeostasis as well as on the serum TH profile by taking advantage of conditional Mct8 mouse mutants expressing cre-recombinase in a cell-specific manner. We will particularly study the consequence of a cell-specific inactivation of Mct8 in the liver, thyroid gland, and the kidney as all three tissues are greatly affected by Mct8 deficiency and have been suggested to be involved in the generation of the abnormal serum TH levels. In addition, we aim to dissect the cell-specific function of Mct8 in the hypothalamus where Mct8 is present in neurons, capillary cells and tanycytes. We further include in our studies mouse mutants that are also deficient in the thyroid hormone transporter Mct10 as our analysis using conventional Mct8/Mct10 deficient mouse mutants indicated a concerted action of both TH transporters in the kidney, liver and thyroid. Most importantly, inactivation of Mct10 leads to a partial normalization of the abnormal serum TH levels characteristic for Mct8 deficiency, and by using conditional mouse mutants we aim to unravel the underlying mechanism.In summary, we aim to elucidate the significance of Mct8 and Mct10 in facilitating TH access to its target tissue and to further elucidate mechanisms that cause the abnormal serum thyroid parameters in Mct8 deficient mice. We also hope our studies will provide an insight to ameliorate the devastating conditions of patients with MCT8 mutations