Manganese-Induced Neurotoxic Effects Research in South Africa (MINERS)
南非锰诱发的神经毒性效应研究 (MINERS)
基本信息
- 批准号:9768467
- 负责人:
- 金额:$ 56.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAffectAstrocytesAutopsyBasal GangliaBrainCell CountChronicCognitiveCollaborationsCorpus striatum structureDataDoseDynaminEnvironmental and Occupational ExposureEtiologyExposure toFunctional disorderGlobus PallidusHealthHumanImmunofluorescence MicroscopyImpaired cognitionInductively Coupled Plasma Mass SpectrometryInflammation MediatorsInflammatoryInjuryMagnetic Resonance ImagingManganeseMediatingMetalsMethodsMicrogliaMiningMitochondrial ProteinsMotorNADPH OxidaseNOS2A geneNeuronsNeurotoxinsOccupationalOutcomePathologicPoliciesPopulationProteinsResearchResearch DesignSignal TransductionSouth AfricaSouth AfricanStainsSubstantia nigra structureTissuesUniversitiesWorkbrain pathwaybrain tissuedensityfollow-upin vivoinnovationmortalinmotor disorderneuroinflammationneuropathologyneurotoxicneurotoxicitynovelolfactory bulbpars compactaprogramsputamenresponse
项目摘要
Abstract
Manganese (Mn) is an established neurotoxicant that affects motor and cognitive brain pathways. This
proposal builds on a growing body of Mn neurotoxicity research generated by our investigative team and
others. Despite these important contributions to studying the health effects of Mn exposure in vivo, defining
the associated neuropathology is essential to understand mechanisms of injury and to characterize dose-
response relations that will inform regulatory policy. These types of studies are extremely challenging due to
the difficulty in acquiring human brain tissue and quantifying lifetime exposure to Mn in the same subjects.
Over the last seven years, we have developed a collaboration with the University of the Witwatersrand in
Johannesburg, South Africa using the only population-wide, occupational autopsy program in the world.
Through this collaboration we have conducted novel preliminary Mn neuropathology studies that support the
aims in this proposal. Our data suggest that chronic, low-level Mn exposure in these mines is associated with
lower neuronal density and higher microglial/astrocyte ratios in the caudate and putamen, indicating that Mn
exposure may cause astrocytic dysfunction which in turn induces a pro-inflammatory neurotoxic state in the
corpus striatum (caudate, putamen, globus pallidus), driven by the activation of microglia. Astrocytic
dysfunction is likely attributable, in part, to dysregulation of several key mitochondrial proteins induced by Mn
exposure. However, our preliminary studies also suggest that Mn mineworkers, with high MRI signal intensity
on T1 MRI, have similar corpus striatal tissue Mn concentrations, but possibly lower Fe concentrations, than
non-Mn mineworkers. In this proposal, we will follow-up on these preliminary data by collecting brains from
deceased Mn mineworkers with contemporaneous Mn exposures and appropriately matched non-Mn
mineworkers. We will use unbiased stereologic methods to quantify neurons, astrocytes, and microglia in the
caudate, putamen, globus pallidus, substantia nigra pars compacta (SNpc), and olfactory bulbs in both groups
of workers and investigate the overall and dose-response associations between these counts and cumulative
Mn exposure. We will also use immunofluorescence microscopy to quantify targeted astrocytic mitochondrial
proteins and inductively coupled plasma-mass spectrometry to compare corpus striatal Mn and Fe
concentrations between groups. This highly innovative study will provide a rare opportunity to advance the
field of Mn neurotoxicity by investigating the neuropathologic effects of chronic Mn exposure.
摘要
锰(Mn)是一种公认的神经毒物,影响运动和认知脑通路。这
该提案建立在我们的调查团队产生的越来越多的锰神经毒性研究的基础上,
他人尽管这些重要的贡献,研究健康的影响锰暴露在体内,定义
相关的神经病理学对于理解损伤机制和表征剂量是必不可少的,
反应关系,将告知监管政策。这些类型的研究极具挑战性,因为
获取人脑组织和量化同一受试者终生暴露于锰的难度。
在过去的七年里,我们与威特沃特斯兰德大学合作,
南非约翰内斯堡使用世界上唯一的全民职业尸检项目。
通过这种合作,我们进行了新的初步锰神经病理学研究,支持
在这个提案中。我们的数据表明,在这些矿山慢性低水平锰暴露与
尾状核和壳核中神经元密度较低,小胶质细胞/星形胶质细胞比率较高,表明Mn
暴露可能导致星形胶质细胞功能障碍,这反过来又诱导了促炎性神经毒性状态,
纹状体(尾状核、壳核、苍白球),由小胶质细胞的激活驱动。星形细胞
功能障碍可能部分归因于锰诱导的几种关键线粒体蛋白的失调,
exposure.然而,我们的初步研究也表明,锰矿工,具有高MRI信号强度,
在T1 MRI上,具有相似的纹状体组织Mn浓度,但可能低于Fe浓度,
无锰矿工在这项提案中,我们将通过收集大脑来跟踪这些初步数据,
死亡锰矿工与同期锰暴露和适当匹配的非锰
矿工我们将使用无偏的体视学方法来定量神经元,星形胶质细胞和小胶质细胞在
尾状核、壳核、苍白球、黑质和嗅球
并调查这些计数和累积剂量之间的总体和剂量反应关系
锰暴露。我们还将使用免疫荧光显微镜定量靶向星形胶质细胞线粒体
蛋白质和电感耦合等离子体质谱比较纹状体锰和铁
组间浓度。这项极具创新性的研究将提供一个难得的机会,
通过研究慢性锰暴露的神经病理学效应,探讨锰的神经毒性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Brad A Racette其他文献
Pregnancy in multiple system atrophy: a case report
- DOI:
10.1186/1752-1947-5-599 - 发表时间:
2011-12-30 - 期刊:
- 影响因子:0.800
- 作者:
Lirong Zhu;Nigel J Cairns;Samer D Tabbal;Brad A Racette - 通讯作者:
Brad A Racette
Brad A Racette的其他文献
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{{ truncateString('Brad A Racette', 18)}}的其他基金
Imaging Biomarkers of Neurotoxicity in Welders
焊工神经毒性的成像生物标志物
- 批准号:
10747199 - 财政年份:2023
- 资助金额:
$ 56.08万 - 项目类别:
Imaging Biomarkers of Neurotoxicity in Welders
焊工神经毒性的成像生物标志物
- 批准号:
10659057 - 财政年份:2023
- 资助金额:
$ 56.08万 - 项目类别:
Manganese-Induced Neurotoxic Effects Research in South Africa
南非锰诱发的神经毒性作用研究
- 批准号:
10805968 - 财政年份:2023
- 资助金额:
$ 56.08万 - 项目类别:
Manganese-Induced Neurotoxic Effects Research in South Africa (MINERS)
南非锰诱发的神经毒性效应研究 (MINERS)
- 批准号:
10242754 - 财政年份:2017
- 资助金额:
$ 56.08万 - 项目类别:
Motor and Cognitive Health Outcomes in a Mn-Exposed African Community
接触锰的非洲社区的运动和认知健康结果
- 批准号:
8975835 - 财政年份:2015
- 资助金额:
$ 56.08万 - 项目类别:
Motor and Cognitive Health Outcomes in a Mn-Exposed African Community
接触锰的非洲社区的运动和认知健康结果
- 批准号:
9115153 - 财政年份:2015
- 资助金额:
$ 56.08万 - 项目类别:
Motor and Cognitive Health Outcomes in a Mn-Exposed African Community
接触锰的非洲社区的运动和认知健康结果
- 批准号:
9236970 - 财政年份:2015
- 资助金额:
$ 56.08万 - 项目类别:
Risk of Parkinson Disease Associated with Solvent Exposures in Finland
芬兰与溶剂接触相关的帕金森病风险
- 批准号:
8752056 - 财政年份:2014
- 资助金额:
$ 56.08万 - 项目类别:
Risk of Parkinson Disease Associated with Solvent Exposures in Finland
芬兰与溶剂接触相关的帕金森病风险
- 批准号:
8916722 - 财政年份:2014
- 资助金额:
$ 56.08万 - 项目类别:
Imaging Biomarkers of Neurotoxicity in Welders
焊工神经毒性的成像生物标志物
- 批准号:
8593295 - 财政年份:2012
- 资助金额:
$ 56.08万 - 项目类别:
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