Role of Manganese in Neurodegenrative Disease

描述（由申请人提供）：最近的研究表明，慢性 暴露于锰（Mn）与增加的风险有关， 神经退行性疾病的发展，如帕金森症。关切 低水平但慢性锰暴露的潜在神经毒性增加， 将MMT掺入汽油中。锰暴露对小鼠的影响 体内啮齿动物模型集中于Mn诱导的纹状体多巴胺消耗， 而非人类灵长类动物的研究更普遍地显示， 苍白球此外，大多数研究使用相对高的Mn暴露， 而只有少数人研究了慢性低水平锰的影响， 暴露。在这里，我们提出，锰毒性的位点可能取决于 总的累积Mn剂量，使得更敏感的GABA能系统的 苍白球的靶向相对剂量较低，而多巴胺能 黑质-纹状体通路系统在较高剂量下参与。到 为了验证这一点，需要研究Mn对特定的 脑核团和神经递质系统作为锰暴露方案的函数 为了更好地表征基底神经节的总体易感性 Mn的影响。此外，人们有理由担心， 低水平的锰暴露可能进一步破坏基底的功能， 神经退行性疾病早期易感人群中的神经节 疾病，并加速神经运动功能障碍的出现。具体 本研究的目的是：（1）确定锰对脑的影响过程 区域锰分布，以及神经化学和神经运动功能， 不同持续时间和低剂量锰暴露的整体动物 啮齿动物模型。以及（2）确定以下因素的影响和潜在相互作用： 锰暴露对啮齿动物模型神经毒性和神经运动性能的影响 无症状帕金森综合征，作为易感人群的模型。这些目标 将通过几个次级目标来实现， 结果：（i）神经运动功能观察组合（FOB） （二）现场的粒子诱发X射线发射分析; 脑区域Mn水平;（iii）GABA能和 特定脑区域中的多巴胺能代谢/状态，和;（iv） 使用放射性同位素研究Mn-GABA能效应的具体机制 细胞培养模型这些拟议的研究将大大扩展我们的 慢性低水平锰神经毒性的知识，通过追求统一的 低水平慢性锰暴露的作用假说，并通过调查 锰暴露的神经化学和神经运动结果与 中度阈下帕金森症

DESCRIPTION (provided by applicant): Recent studies have shown that chronic exposures to manganese (Mn) are associated with an increased risk for the development of neurodegenerative diseases, such as Parkinsonism. Concern over the potential neurotoxicity of low but chronic Mn exposure has increased in light of the incorporation of MMT into gasoline. The effects of Mn exposure in in vivo rodent models has focused on Mn-induced depletion of striatal dopamine, whereas non-human primate studies have more commonly shown gliosis in the globus pallidus. Also, most studies have utilized relatively high Mn exposures, while only a few have investigated the effects of chronic low-level Mn exposures. Here we are proposing that the locus of Mn toxicity may depend on the total cumulative Mn dose, such that more sensitive GABAergic systems of the globus pallidus are targeted at lower relative doses, while dopaminergic systems of the nigro-striatal pathway become involved at higher doses. To validate this, there is a need to investigate the effects of Mn on specific brain nuclei and neurotransmitter systems as a function of Mn exposure regimens in order to better characterize the overall susceptibility of the basal ganglia to Mn effects. Moreover, there is justified concern that increased chronic low-level Mn exposure may further undermine the functionality of the basal ganglia in susceptible populations in the early stages of neurodegenerative disease, and accelerate the emergence of neuromotor dysfunction. The specific aims of this study are to: (1) Determine the progression of Mn effects on brain regional Mn distribution, and neurochemical and neuromotor function, across different durations and low level doses of Mn exposures in a whole animal rodent model. And (2) Determine the effect(s) and underlying interaction(s) of Mn exposure on neurotoxicity and neuromotor performance in a rodent model of asymptomatic Parkinsonism, as a model of a susceptible population. These Aims will be pursued through several sub-aims focusing on the following major outcomes: (i) A Functional Observational Battery (FOB) of neuromotor performance; (ii) Particle induced X-ray emission (PIXE) analyses of in situ brain regional Mn levels; (iii) Neurochemical measures of GABAergic and dopaminergic metabolism/status in specific brain regions, and; (iv) Investigation of specific mechanisms underlying the Mn - GABAergic effect using cell culture models. These proposed studies will significantly extend our knowledge of chronic low level Mn neurotoxicity, by pursuing a unifying hypothesis of action of low-level chronic Mn exposure, and by investigating neurochemical and neuromotor outcomes of Mn exposure in conjunction with a moderate degree of sub-threshold Parkinsonism.