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:10042289
- 负责人:
- 金额:$ 22.4万
- 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:AddressAffectAmphibiaAnimal ModelAnimalsBig DataBiologicalBiological ModelsBiologyBrainCell physiologyCessation of lifeClinical TrialsComparative BiologyComparative StudyCoupledDataDetectionDevelopmental ToxicantDoseEnvironmental PollutionExposure toGoalsHealthHypothalamic structureLinkMeasuresModelingMovement DisordersNematodaNerve DegenerationNeurobiologyNeurodegenerative DisordersNeurologicNeurotransmittersOutcomeParkinson DiseasePathogenesisPathogenicityPathway interactionsPhasePhenotypePhylogenetic AnalysisPlasmaRanaResearchResearch Project GrantsRiskRisk FactorsRodentRodent ModelRoleSystemTestingTherapeuticTissuesTranslationsUrsidae Familybioaccumulationcomparativedisorder riskdopaminergic neurondosagehigh rewardhigh riskinnovationnervous system disorderneurobehavioralneuropathologyneurotoxicityneurotransmissionnoveloxidative damageperfluorooctane sulfonatepituitary thyroid axisprotein aggregationresilienceresponsespecies differencesuccess
项目摘要
Parkinson's disease (PD) is a debilitating movement disorder (affecting ~5 million world‐wide) resulting from
selective death of dopamine (DA) neurons. To date, numerous rarely encountered exposures have been
investigated as risk factors, but none have been clearly linked to PD. Further, the translation of therapeutics that
are promising in animal studies to successful clinical trials has been very poor. These gaps in the field suggest
serious weaknesses in the utilization of animal models in PD research. Most PD studies test hypotheses in single
model systems. However, there are clear advantages with respect to increasing the strength of the findings and
advancing the field through understanding species differences. This R21 aims to be highly responsive to PAR‐
17‐039 (Comparative Biology of Neurodegeneration) by testing PD‐relevant neurodegeneration across three
phylogenetically diverse animal model systems. In the spirit of an R21, the proposal utilizes high risk/high
reward approaches, where novel risk factors will be tested to advance the understanding of the biology of PD.
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
mechanistic and neuropathology data in nematode and amphibian models suggest that exposure to PFAS,
especially perfluorooctane sulfonate (PFOS) induces selective PD‐relevant, DAergic neurotoxicity. This project
will address an important gap on how PFAS exposure leads to long‐term neurological disease risk. We will test
the hypothesis: that species‐specific responses to PFOS‐induced dopaminergic neurodegeneration will advance
understanding of the biology of PD. Importantly, the hypothesis will be 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. We will test our hypothesis through 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 selective dopaminergic
neurotoxicity induced by PFOS exposure. We will conduct comparative biology studies that are both phenotypic
and mechanistic. Resultant data will be critical in determining: 1) Which species is best suited to PFOS
neurodegeneration studies; 2) Identifying which pathogenic pathways directly correlate with
neurodegeneration across species. These studies will mechanistically advance the field far beyond data from
typical single‐species studies.
帕金森病(PD)是一种使人衰弱的运动障碍(全球约有500万人受到影响)
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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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:
$ 22.4万 - 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:
$ 22.4万 - 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:
10289079 - 财政年份:2020
- 资助金额:
$ 22.4万 - 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:
$ 22.4万 - 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:
$ 22.4万 - 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:
$ 22.4万 - 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:
$ 22.4万 - 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:
$ 22.4万 - 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:
$ 22.4万 - 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:
$ 22.4万 - 项目类别:
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