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) 是正常生长和发育所需的必需但未被充分重视的营养素。 发展。锰对于线粒体产生活性氧是必需的，这对于 细胞存活。尽管锰在人体中发挥着广泛的作用，但大脑似乎是最敏感的器官 锰失调。最近的流行病学调查发现，低锰水平和高锰水平都与 儿童认知和行为障碍。此外，接触高浓度的锰会导致大脑 锰积累和帕金森样疾病。因此，锰失调与大脑之间的相关性 人类的功能障碍是众所周知的。但两者之间的因果关系仍有待考证 决定。锰水平异常是否会导致认知发育受损？大脑发育为何如此 对锰失调敏感？缺乏可以操纵锰水平的实验方法 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帮助理解锰的调节 是正常和病理性大脑发育和功能的基础。我的研究小组和其他人最近 发现了溶质载体家族 39 成员 8 (SLC39A8) 在 Mn 稳态中的作用，该作用与 神经发育。 SLC39A8 是一种跨膜金属离子转运蛋白，已知可转运各种金属 例如锌、铁、镉、硒和锰。 2015年，SLC39A8突变被报道于 以智力障碍和脑萎缩为特征的神经发育障碍（NDD）。尤其， 携带 SLC39A8 突变的患者的血液中锰含量极低，但这些患者体内的其他金属含量却很低。 患者均正常。我的研究小组证明，与疾病相关的突变消除了 Mn 摄取活性和线粒体功能受损。在这些研究中，锰水平的主要扰动 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 体内稳态，并且 Mn 是体内需要 SLC39A8 的主要底物。目前SLC39A8如何不足 NDD 的贡献仍然未知。 该项目的目标是建立一个小鼠模型，我们可以用它来探索锰在 神经元。我们已经生成了 Slc39a8 神经元特异性敲除 (Slc39a8-NSKO) 小鼠，其中 Slc39a8 特别是在神经元中被删除。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，因为缺乏对神经元内锰水平的控制 先例;因此，该项目与R21机制非常契合。完成这些目标可能会提供 第一个探索锰在神经元中作用的小鼠模型。因此，这项研究将为 研究大脑中的锰稳态，并更好地了解锰相关 NDD 的病因学， 这可能会导致开发治疗策略的新方法。