PFOS-induced dopaminergic neurodegeneration across nematode, amphibian, and rodent models
线虫、两栖动物和啮齿动物模型中全氟辛烷磺酸诱导的多巴胺能神经变性
基本信息
- 批准号:10289079
- 负责人:
- 金额:$ 30.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdministrative SupplementAlzheimer&aposs DiseaseAmphibiaAnimal ModelBiochemicalBiologicalBiological ModelsBiologyBloodBrainBrain regionCell modelCellsComparative BiologyComparative StudyDataDementiaDevelopmentDevelopmental ToxicantDoseEnvironmental ExposureEnvironmental PollutionEventExposure toFundingGoalsGrantHippocampus (Brain)HistologicHumanLiteratureMeasuresModelingNational Institute on AgingNematodaNerve DegenerationNeurobiologyNeurologicNeurotransmittersParkinson DiseasePathogenicityPathologyPathway interactionsPhenotypePlasmaProteinsRanaRiskRisk FactorsRodentRodent ModelStainsSystemTestingTissuesUnited States National Institutes of HealthUrsidae FamilyVertebratesabeta accumulationdisease phenotypedisorder riskdosageepidemiology studyexperimental studynervous system disorderneurobehavioralneurochemistryneuropathologyneurotoxicneurotoxicityoxidative damageperfluorooctane sulfonateprogramsprotein aggregationresponsespecies differencetau Proteinstau aggregationvirtual
项目摘要
R21AG068787 is entitled, “PFOS-induced dopaminergic neurodegeneration across nematode, amphibian, and
rodent models”. The primary focus is on Parkinson’s disease (PD) endpoints as part of NIA’s Comparative
Biology of Neurodegeneration (to PAR-17-039) program. Per- and polyfluoroalkyl substances (PFAS) are
widespread environmental contaminants that have been investigated as developmental toxicants, with little
information on long-term neurotoxicity. Our preliminary data in nematode and amphibian models suggest that
exposure to PFAS, especially perfluorooctane sulfonate (PFOS) induces neurotoxicity. The main project
addresses an important gap on how PFAS exposure leads to long-term neurological disease risk through testing
the following hypothesis: that species-specific responses to PFOS-induced dopaminergic neurodegeneration will
advance understanding of the biology of PD. This hypothesis is being tested across 3 animal model systems,
where concordance will strengthen findings, and discordance will identify biological aspects of species-specific
sensitivity to environmentally induced neurodegeneration. The funded project has two aims: Aim 1. To identify
species specific-PFOS doses that induce DAergic neurodegeneration. PFOS doses will be harmonized across
systems to achieve brain levels that bear environmental relevance. Harmonization of internal dose levels to set
external applied dosages for each model system will allow us to interrogate mechanistic hypothesis under
comparable insults; Aim 2. Identify neurobiological underpinnings across species that contribute to differential
sensitivity to PFOS-induced dopaminergic neurodegeneration. Here, we will identify species-specific
differences in neurodegeneration that may underlie critical aspects of neurotoxicity induced by PFOS exposure.
Throughout our examination of the PFAS literature, along with our own preliminary data newly collected from
R21AG068787, it has become apparent that Alzheimer’s disease (AD)-relevant expansion is strongly supported.
PFAS (specifically PFOS) exposure produces modulation of several critical AD proteins in multiple model
systems. Thus, in an effort to be highly responsive to NOT-AG-20-034 (entitled, “Alzheimer’s-focused
administrative supplements for NIH grants that are not focused on Alzheimer’s disease”), we will leverage
R21AG068787 to test the following hypothesis that is aimed at exploring overlap between AD and PD: PFOS
exposure will produce an AD-relevant phenotype and that species-specific responses will advance
understanding of the biology of AD. This supplement leverages the original scope, adding AD-relevant
endpoints, where amyloid beta aggregation, tau aggregation/hyperphosphorylation and other key AD
biochemical events will be assessed. Furthermore, AD-relevant neurobehavioral analyses are added in this
supplement. Given PFAS exposures are widespread (detectable in >99% of human blood), it is critical to
determine if such exposures represent a neurological risk. Our supplement will determine whether PFOS
produces neuropathology relevant to AD and identify neurotoxic overlap between AD and PD phenotypes.
R21 AG 068787的标题为“PFOS-induced dopaminergic neurodegeneration across nematode,amphipian,and
啮齿动物模型”。主要重点是帕金森病(PD)终点,作为NIA比较研究的一部分。
神经变性生物学(PAR-17-039)程序。全氟烷基和多氟烷基物质(PFAS)是
广泛存在的环境污染物已被调查为发育毒物,
关于长期神经毒性的信息。我们在线虫和两栖动物模型中的初步数据表明,
接触全氟辛烷磺酸,特别是全氟辛烷磺酸(PFOS)可引起神经毒性。主体工程
通过测试解决了PFAS暴露如何导致长期神经系统疾病风险的重要差距
以下假设:对全氟辛烷磺酸诱导的多巴胺能神经变性的物种特异性反应
进一步了解PD的生物学。这一假设正在3种动物模型系统中进行测试,
一致性将加强发现,不一致性将确定物种特异性的生物学方面,
对环境诱导的神经变性的敏感性。该项目有两个目标:目标1。以识别
特定物种-诱发DA能神经变性的全氟辛烷磺酸剂量。全氟辛烷磺酸剂量将统一
系统来达到与环境相关的大脑水平。内部剂量水平与设定值的协调
每个模型系统的外部应用剂量将使我们能够在
相似的侮辱;目标2.确定跨物种的神经生物学基础,
对全氟辛烷磺酸引起的多巴胺能神经变性的敏感性。在这里,我们将确定物种特异性
神经退化的差异可能是全氟辛烷磺酸暴露引起的神经毒性的关键方面的基础。
在我们对PFAS文献的研究中,沿着我们自己的初步数据,
R21 AG 068787中,已经变得明显的是,阿尔茨海默病(AD)相关的扩展得到了强烈支持。
PFAS(特别是PFOS)暴露在多种模型中对几种关键AD蛋白产生调节
系统.因此,为了高度响应于NOT-AG-20-034(题为“阿尔茨海默氏症集中的
美国国立卫生研究院赠款的行政补充,不集中在阿尔茨海默病”),我们将利用
R21 AG 068787,以检验以下旨在探索AD和PD之间重叠的假设:
暴露将产生AD相关表型,并且物种特异性反应将提前
了解AD的生物学。本补充文件利用了原始范围,添加了广告相关
终点,其中淀粉样蛋白β聚集、tau聚集/过度磷酸化和其他关键AD
将评估生化事件。此外,本研究还增加了AD相关的神经行为分析。
补充.考虑到PFAS的广泛暴露(在>99%的人体血液中可检测到),
确定这种暴露是否代表神经风险。我们的补充将决定全氟辛烷磺酸
产生与AD相关的神经病理学,并鉴定AD和PD表型之间的神经毒性重叠。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Neurotransmission Targets of Per- and Polyfluoroalkyl Substance Neurotoxicity: Mechanisms and Potential Implications for Adverse Neurological Outcomes.
- DOI:10.1021/acs.chemrestox.2c00072
- 发表时间:2022-08-15
- 期刊:
- 影响因子:4.1
- 作者:Brown-Leung, Josephine M.;Cannon, Jason R.
- 通讯作者:Cannon, Jason R.
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Jason R Cannon其他文献
Jason R Cannon的其他文献
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{{ truncateString('Jason R Cannon', 18)}}的其他基金
Mechanisms of PhIP-induced dopaminergic neurotoxicity
PhIP 诱导多巴胺能神经毒性的机制
- 批准号:
10595271 - 财政年份:2023
- 资助金额:
$ 30.85万 - 项目类别:
PFOS-induced dopaminergic neurodegeneration across nematode, amphibian, and rodent models
线虫、两栖动物和啮齿动物模型中全氟辛烷磺酸诱导的多巴胺能神经变性
- 批准号:
10042289 - 财政年份:2020
- 资助金额:
$ 30.85万 - 项目类别:
PFOS-induced dopaminergic neurodegeneration across nematode, amphibian, and rodent models
线虫、两栖动物和啮齿动物模型中全氟辛烷磺酸诱导的多巴胺能神经变性
- 批准号:
10241311 - 财政年份:2020
- 资助金额:
$ 30.85万 - 项目类别:
Mechanisms of PhIP-induced dopaminergic neurotoxicity
PhIP 诱导多巴胺能神经毒性的机制
- 批准号:
9104730 - 财政年份:2016
- 资助金额:
$ 30.85万 - 项目类别:
PhIP-induced neurodegeneration: mechanisms and relevance to Parkinson's disease
PhIP 诱导的神经变性:机制及其与帕金森病的相关性
- 批准号:
8643407 - 财政年份:2014
- 资助金额:
$ 30.85万 - 项目类别:
PhIP-induced neurodegeneration: mechanisms and relevance to Parkinson's disease
PhIP 诱导的神经变性:机制及其与帕金森病的相关性
- 批准号:
8792389 - 财政年份:2014
- 资助金额:
$ 30.85万 - 项目类别:
New Approaches to Gene-environment Interaction Modeling in Parkinson's Disease
帕金森病基因-环境相互作用建模的新方法
- 批准号:
8610308 - 财政年份:2012
- 资助金额:
$ 30.85万 - 项目类别:
New Approaches to Gene-environment Interaction Modeling in Parkinson's Disease
帕金森病基因-环境相互作用建模的新方法
- 批准号:
8350767 - 财政年份:2012
- 资助金额:
$ 30.85万 - 项目类别:
New Approaches to Gene-environment Interaction Modeling in Parkinson's Disease
帕金森病基因-环境相互作用建模的新方法
- 批准号:
8424270 - 财政年份:2012
- 资助金额:
$ 30.85万 - 项目类别:
New Approaches to Gene-environment Interaction Modeling in Parkinson's Disease
帕金森病基因-环境相互作用建模的新方法
- 批准号:
8089751 - 财政年份:2011
- 资助金额:
$ 30.85万 - 项目类别:
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