Pesticide-Mediated Generation of a Toxic Neurotransmitter Metabolite
农药介导的有毒神经递质代谢物的产生
基本信息
- 批准号:10466881
- 负责人:
- 金额:$ 30.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgricultureAldehydesAnimal ModelAreaAstrocytesBasal GangliaCellsChemicalsChlorinated HydrocarbonsChronicComplexDataDevelopmentDieldrinDiseaseDisease ProgressionDopamineDopaminergic CellDoseEnvironmental Risk FactorEnzymesEpidemiologyEtiologyExposure toFunctional disorderGenerationsGeneticGenetic VariationGoalsImpairmentIn VitroIndividualInflammation MediatorsInjuryKnock-outLinkLiteratureMass Spectrum AnalysisMeasuresMediatingMediator of activation proteinMetabolismMolecularMolecular TargetMonoamine OxidaseMonoamine Oxidase BMusNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronal InjuryNeuronsNeurotransmittersNitrogenOxidative StressOxygenParkinson DiseasePathogenicityPathologicPathway interactionsPesticidesProductionProteinsQuinonesReactionResearchRiskRoleTestingToxic effectTransgenic MiceWorkaldehyde dehydrogenasesbasal ganglia injurybasecell typecellular targetingdisease diagnosisdopamine systemdopaminergic neuronearly detection biomarkersenvironmental agentexposed human populationgene environment interactiongenetic approachglial activationin vivoinnovationnervous system disorderneuroinflammationneuron lossneurotoxicneurotoxicityneurotransmitter metabolismnew therapeutic targetoverexpressionpesticide exposurepesticide interactionpotential biomarkerrelease factorresponsestemsynergismtrafficking
项目摘要
PROJECT SUMMARY
Exposure to the organochlorine dieldrin predisposes individuals to Parkinson's Disease (PD); however, the
mechanisms linking exposure to disease and selective loss of dopaminergic cells are unknown. In addition,
dieldrin alone may be insufficient for loss of dopamine (DA) neurons, and neurodegeneration may require an
additional “hit”, such as from genetics. Several animal models have demonstrated that altering DA metabolism
and/or trafficking yields progressive loss of DA neurons; therefore, a genetic variation modifying DA
metabolism may be an additional “hit” that has toxic synergy with pesticide exposure. Cell types other than DA
neurons are thought to be involved in PD, such as glia, and toxic factors released via glial activation are
realized as a critical contributors to disease progression. Both DA neurons and glial cells (e.g., astrocytes)
metabolize DA and other neurotransmitters and generate toxic intermediates such as ROS and aldehydes
(3,4-dihydroxyphenylacetaldehyde, DOPAL), via monoamine oxidase. Based on literature precedent and
preliminary data, we propose DA metabolism and trafficking as a mechanistic target for the pesticide dieldrin
that can produce a build-up of reactive and toxic intermediates such as DOPAL and neuroinflammation. While
the role of DA and its quinone have been explored as a mechanism for neurotoxicity, very little is known about
DOPAL and the role of aldehyde metabolism. DOPAL generation is proposed as a mechanism unifying
pesticide exposure, neuroinflammation and loss of catecholaminergic cells. The goal of this work is to elucidate
mechanisms underlying environmental risk factors for neurodegenerative disease, specifically focusing on the
interaction of the pesticide dieldrin with DArgic and glia and resulting injury to dopaminergic neurons via
reactive intermediates such as DOPAL. In addition, the gene-environment interaction will be explored as
dieldrin alone may be insufficient to cause loss of DA neurons. The central hypothesis is that pesticides such
as dieldrin target DA metabolism and/or trafficking in neurons and glia, yielding reactive aldehyde metabolites
that damage DA neurons and promote neuroinflammatory activation of glial cells. Three Aims will be
completed: 1) Determine the effects of pesticide exposure on the nigro-striatal DA system in transgenic mice
with altered DA metabolism. 2) Determine the contribution of glial-derived reactive DA intermediates to
pesticide-mediated neuronal injury. 3) Identify cellular and molecular targets of reactive intermediates. An
innovative and encompassing approach in vivo and in vitro will be used with a robust genetic strategy of mice
that are deficient or have overexpression of enzymes key to DA metabolism. These Specific Aims will build
upon previous work to address key mechanistic questions regarding critical cellular interactions between
astrocytes and neurons that potentiate dysfunction caused by exposure to pesticides.
项目摘要
暴露于有机氯的二肽蛋白使个体患有帕金森氏病(PD);但是,
将暴露与疾病接触和多巴胺能细胞的选择性丧失联系起来的机制尚不清楚。此外,
单独的dieldrin可能不足以丧失多巴胺(DA)神经元,而神经变性可能需要
其他“命中”,例如遗传学。几种动物模型表明,改变DA代谢
和/或贩运会导致DA神经元的逐渐丧失;因此,一种修饰DA的遗传变异
代谢可能是一种额外的“命中”,它与暴露于农药的有毒协同作用。除了DA以外的细胞类型
人们认为神经元参与PD,例如神经胶质,而通过神经胶质激活释放的有毒因素是
意识到疾病进展的关键因素。 DA神经元和神经胶质细胞(例如,星形胶质细胞)
代谢DA和其他神经递质,并产生有毒的中间体,例如ROS和醛
(3,4-二羟基苯基乙醛,多巴尔),通过氧化胺单胺。基于文学先例和
初步数据,我们提出DA代谢和贩运作为农药dieldrin的机械目标
这可以产生反应性和有毒中间体(例如多体和神经炎症)的积累。尽管
DA及其喹酮的作用已被探讨为神经毒性的机制,对
多巴尔和醛代谢的作用。提出了多巴尔生成作为统一的机制
农药暴露,神经炎症和儿茶酚胺能细胞的丧失。这项工作的目的是阐明
神经退行性疾病的环境风险因素的基础机制,特别关注
农药dieldrin与dargic和glia的相互作用,以及导致多巴胺能神经元的损伤
反应性中间体,例如多巴尔。另外,将探讨基因环境相互作用
单独的dieldrin可能不足以引起DA神经元的丧失。中心假设是农药
由于dieldrin靶向DA代谢和/或在神经元和神经胶质中的运输,产生了反应性醛代谢物
损害DA神经元并促进神经胶质细胞的神经炎性激活。三个目标将是
完成:1)确定农药暴露对转基因小鼠的二纹状体DA系统的影响
随着DA代谢的改变。 2)确定神经胶质衍生的反应性DA中间体对
农药介导的神经元损伤。 3)确定反应性中间体的细胞和分子靶标。一个
体内和体外的创新和涵盖方法将与小鼠的强大遗传策略一起使用
酶不足或过表达DA代谢的关键。这些具体目标将建立
以前的工作解决了有关关键细胞相互作用的关键机理问题
星形胶质细胞和神经元可能由暴露于农药引起的功能障碍。
项目成果
期刊论文数量(0)
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JONATHAN A DOORN的其他文献
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{{ truncateString('JONATHAN A DOORN', 18)}}的其他基金
Pesticide-Mediated Generation of a Toxic Neurotransmitter Metabolite
农药介导的有毒神经递质代谢物的产生
- 批准号:
10288070 - 财政年份:2018
- 资助金额:
$ 30.87万 - 项目类别:
Pesticide-Mediated Generation of a Toxic Neurotransmitter Metabolite
农药介导的有毒神经递质代谢物的产生
- 批准号:
10246376 - 财政年份:2018
- 资助金额:
$ 30.87万 - 项目类别:
Pesticide-Mediated Generation of a Toxic Neurotransmitter Metabolite
农药介导的有毒神经递质代谢物的产生
- 批准号:
10089497 - 财政年份:2018
- 资助金额:
$ 30.87万 - 项目类别:
Human Exposure and Toxic Responses to Biomaterials
人体对生物材料的接触和毒性反应
- 批准号:
8399340 - 财政年份:2012
- 资助金额:
$ 30.87万 - 项目类别:
CHARACTERIZATION AND APPLICATIONS OF SERS NANOPARTICLES
SERS纳米粒子的表征及应用
- 批准号:
8361778 - 财政年份:2011
- 资助金额:
$ 30.87万 - 项目类别:
CHARACTERIZATION AND APPLICATIONS OF SERS NANOPARTICLES
SERS纳米粒子的表征及应用
- 批准号:
8169414 - 财政年份:2010
- 资助金额:
$ 30.87万 - 项目类别:
CHARACTERIZATION AND APPLICATIONS OF SERS NANOPARTICLES
SERS纳米粒子的表征及应用
- 批准号:
7956797 - 财政年份:2009
- 资助金额:
$ 30.87万 - 项目类别:
Organochlorine-Mediated Generation of a Dopamine Derived Neurotoxin
有机氯介导的多巴胺衍生神经毒素的产生
- 批准号:
7368337 - 财政年份:2008
- 资助金额:
$ 30.87万 - 项目类别:
Organochlorine-Mediated Generation of a Dopamine Derived Neurotoxin
有机氯介导的多巴胺衍生神经毒素的产生
- 批准号:
7996622 - 财政年份:2008
- 资助金额:
$ 30.87万 - 项目类别:
Organochlorine-Mediated Generation of a Dopamine Derived Neurotoxin
有机氯介导的多巴胺衍生神经毒素的产生
- 批准号:
7539937 - 财政年份:2008
- 资助金额:
$ 30.87万 - 项目类别:
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