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)会增加患高血压的风险 神经退行性疾病的发展，如帕金森氏症。担心…… 慢性低剂量锰暴露的潜在神经毒性在 在汽油中加入蒙脱石的光明。锰暴露对小白鼠的影响 在活体啮齿动物模型中，重点是锰诱导的纹状体多巴胺的耗竭， 而非人类灵长类动物的研究更常见地显示出 苍白球。此外，大多数研究都利用了相对较高的锰暴露， 虽然只有几个人研究了慢性低水平锰的影响 曝光。在这里，我们提出，锰中毒的位置可能取决于 总累积锰剂量，从而使更敏感的GABA能系统 苍白球靶向剂量较低，而多巴胺能 黑质-纹状体通路的系统在较高剂量时会受到影响。至 验证这一点，有必要研究锰对特定的 脑核和神经递质系统对锰暴露方案的影响 为了更好地描述基底节的整体易感性 对MN的影响。此外，人们有理由担心，慢性疾病的增加 低水平的锰暴露可能会进一步破坏基础脑区的功能 神经变性早期易感人群的神经节 疾病，并加速神经运动功能障碍的出现。具体的 本研究的目的是：(1)确定锰对脑的影响 不同地区的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对整个动物的影响 啮齿动物模型。(2)确定影响(S)和潜在互动(S) 锰暴露对大鼠神经毒性和神经运动功能的影响 无症状帕金森氏症，作为易感人群的模型。这些目标 将通过几个分目标来实现，重点放在以下主要方面 结果：(I)神经运动功能观察组(FOB) 性能；(Ii)现场粒子诱导X射线发射(PIXE)分析 脑区锰水平；(Iii)GABA能和 特定脑区的多巴胺能代谢/状态，以及；(Iv) 研究锰-伽玛能效应的具体机制 细胞培养模型。这些拟议的研究将大大延长我们的 通过追求统一的方法，了解慢性低水平锰神经毒性 低水平慢性锰暴露的作用假说及调查 联合接触锰对神经化学和神经运动的影响 中度亚阈值帕金森氏症。

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.