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.
R21AG068787的标题是“全氟辛烷磺酸诱导的跨线虫、两栖动物和
啮齿动物模型“。作为NIA比较的一部分,主要关注帕金森病(PD)终点
神经变性生物学(按PAR-17-039)计划。全氟烷基和多氟烷基物质(PFA)是
作为发育毒物被调查的广泛的环境污染物,几乎没有
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
暴露于全氟辛烷磺酸,尤其是全氟辛烷磺酸(PFOS)会导致神经毒性。主要项目
通过测试解决关于全氟辛烷磺酸暴露如何导致长期神经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将
促进对帕金森病生物学的了解。这一假设正在3个动物模型系统中进行验证,
其中,一致性将加强研究结果,而不一致性将识别特定物种的生物学方面
对环境引起的神经变性的敏感性。受资助的项目有两个目标:目标1.确定
物种特定--全氟辛烷磺酸导致多巴胺能神经变性的剂量。全氟辛烷磺酸的剂量将在
达到与环境相关的大脑水平的系统。协调内部剂量水平以设定
每个模型系统的外部应用剂量将允许我们在以下条件下询问机械假说
类似的侮辱;目标2.确定导致差异的跨物种神经生物学基础
对全氟辛烷磺酸诱导的多巴胺能神经变性的敏感性。在这里,我们将识别特定物种
神经变性的差异可能是全氟辛烷磺酸暴露所致神经毒性的关键方面的基础。
通过我们对PFAS文献的检查,以及我们自己新收集的初步数据
R21AG068787,很明显,阿尔茨海默病(AD)相关的扩展得到了强烈支持。
全氟辛烷磺酸(特别是全氟辛烷磺酸)在多种模型中对几种关键AD蛋白产生调节作用
系统。因此,在努力对NOT-AG-20-034(标题为《聚焦阿尔茨海默氏症》)做出高度响应的努力中
NIH不关注阿尔茨海默氏症的行政补助“),我们将利用
R21AG068787以测试以下旨在探索AD和PD之间重叠的假设:全氟辛烷磺酸
暴露将产生与AD相关的表型,并且特定物种的反应将提前
对阿尔茨海默病生物学的理解。本补充内容利用了原始范围,添加了与AD相关的内容
终末点,其中淀粉样β聚集、tau聚集/过度磷酸化和其他关键AD
将对生化事件进行评估。此外,还增加了与AD相关的神经行为分析
副刊。鉴于PFAS暴露广泛(在99%的人血液中可检测到),至关重要的是
确定这样的暴露是否代表神经风险。我们的增刊将决定全氟辛烷磺酸
产生与AD相关的神经病理学,并确定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:
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:
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:
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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