Role of Manganese in Neurodegenrative Disease

锰在神经退行性疾病中的作用

• 批准号: 6782504
• 负责人: DONALD R SMITH
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6782504
• 关键词: 6 hydroxydopamine; Parkinson' s disease; Rodentias; X ray spectrometry; basal ganglia; behavior test; behavioral /social science research tag; brain mapping; disease /disorder model; disease /disorder proneness /risk; dopamine; dosage; gamma aminobutyrate; manganese; metal poisoning; neural degeneration; neural transmission; neurochemistry; neuromuscular system; neurons; neuropsychology; neurotoxicology; neurotransmitters; pathologic process; tissue /cell culture

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.

描述（由申请人提供）：最近的研究表明，慢性 对锰（MN）的暴露与增加的风险有关 神经退行性疾病的发展，例如帕金森主义。关心 低但慢性MN暴露的潜在神经毒性在 将MMT掺入汽油的光。 Mn暴露在 体内啮齿动物模型集中于Mn诱导的纹状体多巴胺的耗竭， 而非人类的灵长类研究更常见于 Globus Pallidus。而且，大多数研究都使用了相对较高的MN暴露， 虽然只有少数研究了慢性低级MN的影响 暴露。在这里，我们提出MN毒性的轨迹可能取决于 总累积MN剂量，使得更灵敏的GABA能系统 Globus Pallidus的靶向较低的相对剂量，而多巴胺能 黑色 - 纹状体途径的系统以较高剂量涉及。到 验证这一点，需要研究MN对特定的影响 脑核和神经递质系统与MN暴露方案的关系 为了更好地描述基底神经节的整体敏感性 对Mn效应。此外，有合理的关注点增加了慢性 低级MN暴露可能会进一步破坏基础的功能 神经退行性的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 这项研究的目的是：（1）确定MN对脑的影响的进展 区域MN分布以及神经化学和神经运动功能 整个动物的不同持续时间和低剂量的Mn暴露 啮齿动物模型。 （2）确定效果（s）和基础相互作用 Mn在啮齿动物模型中对神经毒性和神经运动性能的暴露 无症状的帕金森氏症，作为易感人群的模型。这些目标 将通过几个专注于以下专业的子iams追求 结果：（i）神经运动的功能性观察电池（FOB） 表现; （ii）粒子诱导的X射线发射（PIXE）原位分析 大脑区域MN水平； （iii）GABA能和GABA能的神经化学测量 特定大脑区域的多巴胺能代谢/状态，以及； （iv） 研究使用Mn -GABA能效应的特定机制的研究 细胞培养模型。这些提出的研究将大大扩展我们的 通过追求统一的慢性低水位MN神经毒性的了解 低级慢性MN暴露的作用假设，并通过研究 MN暴露的神经化学和神经运动结果与A结合 中阈值帕金森氏症的中等程度。