Exploring the Roles of Manganese in Neurons

探索锰在神经元中的作用

• 批准号: 9976232
• 负责人: Young Ah Seo
• 金额: $ 42.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976232
• 关键词: Address; Affect; Animal Model; Animals; Biological; Blood; Brain; Brain region; Cadmium; Cell Culture Techniques; Cell Nucleus; Cell Survival; Cells; Cerebellum; Child; Data; Development; Dietary Manganese; Dietary Supplementation; Disease; Enzymes; Epidemiology; Etiology; Exhibits; Exploratory/Developmental Grant; Exposure to; Family; Generations; Genetic Transcription; Goals; Growth and Development function; Health; Histologic; Histology; Homeostasis; Human; Human body; Impaired cognition; Impairment; Inductively Coupled Plasma Mass Spectrometry; Intellectual functioning disability; Ions; Iron; Knock-out; Knowledge; Lead; Link; Manganese; Manganese Poisoning; Measurement; Measures; Metals; Minor; Mitochondria; Modeling; Molecular; Motor; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Nutrient; Organ; Parkinsonian Disorders; Pathologic; Pathway interactions; Patients; Play; Reactive Oxygen Species; Regulation; Reporting; Research; Role; Selenium; Surveys; Testing; Therapeutic; Tissues; Zinc; behavioral impairment; cell type; cerebral atrophy; cognitive development; in vivo; manganese deficiency; member; motor disorder; mouse model; neurodevelopment; neuron loss; novel strategies; radiotracer; solute; transcriptome; transcriptome sequencing; uptake

ABSTRACT Manganese (Mn) is an essential yet underappreciated nutrient required for proper growth and development. Mn is necessary for mitochondrial generation of reactive oxygen species, which is important for cell survival. Although Mn plays a broad role in the human body, the brain appears to be the most sensitive organ to Mn dysregulation. Recent epidemiological surveys have found that both low and high Mn levels are associated with cognitive and behavioral impairment in children. Moreover, exposure to high levels of Mn can lead to brain Mn accumulation and a parkinsonian-like disorder. Thus, the correlation between Mn dysregulation and brain malfunction in humans is well established. However, the causal relationship between the two remains to be determined. Do abnormal Mn levels result in impaired cognitive development? Why is brain development so sensitive to dysregulation of Mn? The lack of experimental approaches that can manipulate Mn levels in only the brain has been the major roadblock to addressing these important questions. The overarching goal of my research group is to contribute to the understanding of how Mn regulation underlies normal and pathological brain development and functions. My research group and others recently discovered a role for solute carrier family 39, member 8 (SLC39A8) in Mn homeostasis that is linked to neurodevelopment. SLC39A8 is a transmembrane metal-ion transporter that is known to transport various metals such as zinc, iron, cadmium, selenium, and Mn. In 2015, mutations in SLC39A8 were reported in neurodevelopmental disorders (NDDs) characterized by intellectual disabilities and brain atrophy. Notably, patients with SLC39A8 mutations exhibited severely low levels of Mn in the blood, but other metal levels in these patients were normal. My research group demonstrated that the disease-associated mutations abrogated Mn uptake activity and impaired mitochondrial functions. In these studies, the major perturbations in Mn levels contrast strikingly with minor alterations in other metal levels, confirming that SLC39A8 is essential for Mn homeostasis and that Mn is a main substrate that requires SLC39A8 in vivo. At present, how SLC39A8 deficiency contributes NDDs remains unknown. The objective of this project is to establish a mouse model that we can use to explore the roles of Mn in neurons. We have generated Slc39a8 neuron-specific-knockout (Slc39a8-NSKO) mice, in which Slc39a8 is deleted specifically in neurons. We will test whether Slc39a8-NSKO mice are an animal model of neuronal Mn deficiency. The proposed project is exploratory because control of Mn levels specifically within neurons lacks precedent; therefore, the project fits well with the R21 mechanism. Completion of these aims will likely provide the first mouse model to explore the roles of Mn in neurons. As such, this research will open an avenue to the study of Mn homeostasis in the brain and a better understanding of the etiology underlying Mn-related NDDs, which could lead to novel approaches for developing therapeutic strategies.

抽象的 锰（MN）是适当生长和 发展。 Mn对于线粒体生成活性氧必不可少，这对于 细胞存活。尽管MN在人体中起着广泛的作用，但大脑似乎是最敏感的器官 Mn失调。最近的流行病学调查发现，低和高Mn水平均与 儿童的认知和行为障碍。此外，暴露于高水平的MN会导致大脑 MN积累和帕金森氏症疾病。因此，MN失调与大脑之间的相关性 人类的故障已经确定。但是，两者之间的因果关系仍然是 决定。异常的MN水平会导致认知发展受损吗？为什么大脑发育如此 对MN的失调敏感？缺乏仅在仅在 大脑一直是解决这些重要问题的主要障碍。 我的研究小组的总体目标是为理解MN调节做出贡献 基础正常和病理大脑发育和功能。我的研究小组和其他人最近 在MN稳态中发现了Solute Carrier家族39，成员8（SLC39A8）的角色，该角色与与 神经发育。 SLC39A8是一种跨膜金属离子转运蛋白，已知可以运输各种金属 例如锌，铁，镉，硒和MN。 2015年，据报道SLC39A8中的突变 具有智力残疾和脑萎缩为特征的神经发育障碍（NDDS）。尤其， SLC39A8突变的患者在血液中表现出严重低水平的MN，但其他金属水平 患者正常。我的研究小组表明，与疾病相关的突变废除了MN 吸收活性和线粒体功能受损。在这些研究中，MN水平的主要扰动 与其他金属水平的微小变化形成鲜明对比，证实SLC39A8对于MN至关重要 稳态和MN是主要底物，需要在体内Slc39a8。目前，SLC39A8缺乏症如何 贡献NDD仍然未知。 该项目的目的是建立一个鼠标模型，我们可以用来探索MN在 神经元。我们已经产生了SLC39A8神经元特异性敲除（SLC39A8-NSKO），其中SLC39A8为 专门在神经元中删除。我们将测试SLC39A8-NSKO小鼠是否是神经元MN的动物模型 不足。拟议的项目是探索性的，因为对神经元内的MN水平的控制缺乏 先例;因此，该项目与R21机制非常吻合。这些目标的完成可能会提供 第一个探索MN在神经元中角色的小鼠模型。因此，这项研究将为 MN在大脑中的稳态研究以及对MN相关NDD的病因的更好理解， 这可能导致开发治疗策略的新方法。