Cell type-specific inactivation of Mct8 in brain cells: Gene expression, metabolism, morphology

脑细胞中 Mct8 的细胞类型特异性失活：基因表达、代谢、形态

• 批准号: 221166977
• 负责人: Dr. Eva K. Wirth
• 金额: --
• 依托单位: Institut für Biochemie und Molekularbiologie (IBMB)
• 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 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/221166977?language=en
• 关键词: Cell; type; specific; inactivation; Mct8

Thyroid hormone (TH) transporters and among them monocarboxylate transporter 8 (MCT8) are necessary for proper brain development. Mutations in MCT8 lead to a severe form of psychomotor retardation in humans, the Allan-Herndon-Dudley syndrome (AHDS). Patients present with X-linked mental retardation, muscular hypotonia, and disturbed plasma TH levels (high T3, low T4). Mouse models for global Mct8-deficiency have been generated and yielded surprising data. Tissue responses to circulating TH levels depend on transporter expression leading to hepatic TH excess and concomitant pituitary insensitivity to TH. Similarly, biochemical and behavioural data suggest the coexistence of hyper- and hypothyroid regions in the brain. Thus, evidence is accumulating that the neurological deficits in AHDS patients are not simply caused by defective TH uptake into neurons. In order to better understand the neurological and neurobiochemical phenotypes, we want to take into account the complexity of the brain as an organ composed of neurons, astrocytes, oligodendrocytes, and endothelial cells.We will therefore create astrocyte- and neuron-specific Mct8 knockout mice and re-investigate gene expression, energy metabolism, TH metabolism, and dendritic morphology in their brains. We will thus be able to distinguish metabolic impairments caused by astrocytic or neuronal TH insensitivity from a defective blood-brain-barrier in Mct8-deficient mice. Moreover, we will gain new insight into the compartmentalization of cerebral TH metabolism.

甲状腺激素（TH）转运蛋白和其中的单羧酸转运蛋白8 （MCT8）是大脑正常发育所必需的。MCT8的突变会导致人类出现一种严重的精神运动迟缓，即艾伦-赫恩顿-达德利综合征（AHDS）。患者表现为x连锁智力低下，肌肉张力低下，血浆TH水平紊乱（高T3，低T4）。全球mct8缺乏症的小鼠模型已经产生并产生了令人惊讶的数据。组织对循环TH水平的反应依赖于导致肝脏TH过量的转运蛋白表达和伴随的垂体对TH不敏感。同样，生化和行为数据表明大脑中甲状腺亢进和甲状腺低下并存。因此，越来越多的证据表明，AHDS患者的神经功能缺陷不仅仅是由于TH摄取到神经元的缺陷引起的。为了更好地理解神经和神经生化表型，我们希望考虑到大脑作为一个由神经元、星形胶质细胞、少突胶质细胞和内皮细胞组成的器官的复杂性。因此，我们将创建星形胶质细胞和神经元特异性Mct8敲除小鼠，并重新研究其大脑中的基因表达、能量代谢、TH代谢和树突形态。因此，我们将能够在mct8缺陷小鼠中区分由星形细胞或神经元TH不敏感引起的代谢损伤和血脑屏障缺陷。此外，我们将对脑TH代谢的区隔化有新的认识。