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.

摘要 锰（Mn）是一种必需的但未被充分认识的营养素， 发展Mn是线粒体产生活性氧所必需的，这对于 细胞存活虽然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 到神经失调。最近的流行病学调查发现，低和高锰水平都与 认知和行为障碍的儿童。此外，暴露于高水平的锰可导致大脑 锰积累和帕金森样障碍。因此，锰失调与脑 在人类中的故障是公认的。然而，两者之间的因果关系仍有待进一步研究。 测定锰水平异常是否会导致认知发育受损？为什么大脑发育如此 敏感的失调锰？缺乏实验方法，可以操纵锰水平，只有在 大脑一直是解决这些重要问题的主要障碍。 我的研究小组的首要目标是帮助理解锰的调节是如何 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 发现溶质载体家族39，成员8（SLC 39 A8）在Mn稳态中的作用， 神经发育SLC 39 A8是一种跨膜金属离子转运蛋白，已知可转运多种金属 例如锌、铁、镉、硒和Mn。在2015年，SLC 39 A8的突变被报道在 神经发育障碍（NDD），其特征在于智力残疾和脑萎缩。值得注意地是， 具有SLC 39 A8突变的患者在血液中表现出严重低水平的Mn，但这些患者中的其他金属水平 患者正常。我的研究小组证明，疾病相关的突变废除了锰 摄取活性和受损的线粒体功能。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，证实了SLC 39 A8对Mn是必不可少的 内稳态，Mn是体内需要SLC 39 A8主要底物。目前，如何SLC 39 A8缺陷 NDD的贡献仍然未知。 本项目的目的是建立一个小鼠模型，我们可以用来探讨锰在 神经元我们已经产生了Slc 39 a8神经元特异性敲除（Slc 39 a8-NSKO）小鼠，其中Slc 39 a8是 特别是在神经元中缺失。我们将测试Slc 39 a8-NSKO小鼠是否是神经元Mn的动物模型 缺陷拟议的项目是探索性的，因为缺乏对神经元内特定Mn水平的控制。 因此，该项目非常符合R21机制。这些目标的实现可能会提供 第一个探索Mn在神经元中作用的小鼠模型。因此，这项研究将开辟一条通往 研究锰在大脑中的稳态和更好地了解锰相关的NDD的病因， 这可能导致开发治疗策略的新方法。