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

鼠甲状腺激素转运蛋白 Mct8 和 Mct10 的组织特异性作用

• 批准号: 221028883
• 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: Priority Programmes
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/221028883?language=en
• 关键词: tissue; specific; role; murine; thyroid

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

甲状腺激素（TH）的作用和代谢是细胞内的事件，需要运输TH跨质膜。这一过程是促进TH转运单羧酸转运蛋白8（MCT 8）已被最深入的分析。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TH参数相关。我们最近提供了Mct 8缺陷小鼠的详细描述，尽管没有明显的神经系统症状，但表现出与携带MCT 8突变的患者相同的不寻常的血清TH参数。作为改变TH概况以及TH转运在各种器官中的变化的结果，Mct 8 ko小鼠表现出组织特异性TH过量和剥夺的复杂表型，这阻碍了Mct 8的组织特异性作用的分析。在这里，我们的目标是解开的后果，细胞特异性失活的Mct 8组织稳态以及血清TH的配置文件，利用条件Mct 8小鼠突变体表达的cre重组酶在细胞特异性的方式。我们将特别研究Mct 8在肝脏、甲状腺和肾脏中的细胞特异性失活的后果，因为所有这三种组织都受到Mct 8缺乏的极大影响，并且已经被认为参与了异常血清TH水平的产生。此外，我们的目标是解剖细胞特异性功能的Mct 8在下丘脑Mct 8是目前在神经元，毛细血管细胞和伸长细胞。我们进一步包括在我们的研究中，也缺乏甲状腺激素转运蛋白Mct 10的小鼠突变体，因为我们使用常规Mct 8/Mct 10缺陷小鼠突变体的分析表明，在肾脏，肝脏和甲状腺中TH转运蛋白的协同作用。最重要的是，Mct 10的失活导致Mct 8缺陷所特有的异常血清TH水平的部分正常化，并且通过使用条件性小鼠突变体，我们的目标是解开潜在的机制。我们的目的是阐明Mct 8和Mct 10在促进TH进入其靶组织中的意义，并进一步阐明Mct 8缺陷患者血清甲状腺参数异常的机制。小鼠我们也希望我们的研究能为改善MCT 8突变患者的破坏性状况提供一种见解。