Project 3: Cellular and Molecular Mechanisms Underlying Long-term Effects of Early Life Exposure to HAB Toxins
项目 3:生命早期接触 HAB 毒素造成长期影响的细胞和分子机制
基本信息
- 批准号:10223309
- 负责人:
- 金额:$ 14.15万
- 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 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdultAffectAgonistAnimal ModelAnimalsAxonBehaviorBehavioralBehavioral AssayBrainCell LineageCellsChemicalsClimateCollaborationsCommunicationCommunity OutreachDefectDevelopmentDiseaseDoseElderlyEmbryoEnvironmentEnvironmental ExposureEpidemiologyExposure toGene ExpressionGene Expression ProfileGenetic TranscriptionGlutamate ReceptorHealthHumanIon ChannelLarvaLifeLife Cycle StagesLong-Term EffectsMeasuresModelingMolecularMotor NeuronsNervous system structureNeuraxisNeurogliaNeuronsNeurotransmitter ReceptorOceansOligodendrogliaPerinatal ExposurePhysiologicalProtein FamilyPublic HealthRegulationResearchRiskRodentSafetySaxitoxinSeafoodSignal TransductionSodium ChannelTestingToxic effectToxinTransgenic OrganismsVisualizationWood materialZebrafishacute toxicityaxon growthbaseclimate changecognitive functioncommunity engagementdesigndevelopmental neurotoxicitydevelopmental toxicitydomoic acidearly life exposureexperimental studyexposed human populationharmful algal bloomshuman modelinhibitor/antagonistmigrationmyelinationneurobehaviorneurobehavioralneurodevelopmentneurotoxicityneurotoxicologynoveloligodendrocyte lineageoligodendrocyte myelinationprenatalpreventstressorvoltage
项目摘要
The overall objective of the proposed research is to elucidate the cellular and molecular mechanisms by which
early-life exposure to harmful algal bloom (HAB) toxins may interfere with neurodevelopment to cause
persistent neurobehavioral changes later in life. The HAB toxins domoic acid and saxitoxin occur in seafood
and levels are regulated to prevent acute toxicity. However, human exposure to these toxins at levels below
regulatory limits is common, widespread, and may be increasing, posing risks to vulnerable subpopulations
such as developing humans. It is now well known that the early life environment can profoundly influence
health throughout the life course (the developmental origins of health and disease). However, the mechanisms
by which developmental exposures elicit effects later in life are not well understood. The central hypothesis of
this research is that early life, low-level exposure to domoic acid and saxitoxin targets neurotransmitter
receptors and ion channels, leading to altered gene expression, functional changes in glial and neural cells,
and long-term changes in neurobehavioral function in adults. These studies will be conducted using zebrafish,
a powerful model organism in developmental neurotoxicology research. In Aim 1, we will test the hypothesis
that embryonic exposure to low levels of domoic acid, a glutamate receptor agonist, targets developing
oligodendrocytes (OLs), thereby disrupting myelination of axons. We will measure the effects on OL-lineage
cells using a variety of transgenic zebrafish lines that allow visualization of developing OLs and myelination.
We will elucidate the functional consequences of these changes by assessing larval behavior. In addition, we
will determine later life consequences of developmental exposure to domoic acid on neurobehavior using a
battery of well-established behavioral assays and characterizing the gene expression patterns in the adult
brain. In Aim 2, we will test the hypothesis that developmental exposure to saxitoxin, an inhibitor of voltage-
gated sodium channels, targets developing neurons, leading to defects in axonal growth. We will visualize the
changes in axonal growth in motor neurons and determine functional changes in larval and adult behavior. In
Aim 3, we will test the hypothesis that combined early life exposure to low levels of domoic acid and saxitoxin
targets OLs and neuronal cells, interfering with activity-dependent myelination and causing enhanced deficits
in myelination and neurobehavior. We will also test the hypothesis that domoic acid and saxitoxin can cause
silent neurotoxicity that can be unmasked later in life by secondary stressors. Research in collaboration with
Projects 1 and 2 and the Community Outreach Core will model human exposure and how it may change with a
changing climate. This research will identify the cellular and molecular bases for neurobehavioral effects
following early-life exposure to prominent HAB toxins, contributing to an understanding of the potential long-
term health consequences of developmental exposure to domoic acid and saxitoxin in humans, critical for
assessing public health risks associated with the possibly increasing exposure to these toxins.
这项研究的总体目标是阐明细胞和分子机制,
生命早期暴露于有害藻华(HAB)毒素可能会干扰神经发育,
在以后的生活中持续的神经行为变化。赤潮毒素软骨藻酸和石房蛤毒素存在于海产品中
并调节水平以防止急性毒性。然而,人类接触这些毒素的水平低于
监管限制是常见的、广泛的,并且可能会增加,对脆弱的亚群构成风险
比如发展人类。现在大家都知道,早期的生活环境可以深刻地影响
健康贯穿整个生命过程(健康和疾病的发展起源)。然而,机制
发育性接触对以后生活的影响尚不清楚。的中心假设
这项研究表明,生命早期,低水平暴露于软骨藻酸和石房蛤毒素的目标神经递质
受体和离子通道,导致基因表达改变,神经胶质细胞和神经细胞的功能变化,
以及成年人神经行为功能的长期变化。这些研究将使用斑马鱼进行,
发育神经毒理学研究中的一种强有力的模式生物。在目标1中,我们将检验假设
胚胎暴露于低水平的软骨藻酸(一种谷氨酸受体激动剂),
少突胶质细胞(OL),从而破坏轴突的髓鞘形成。我们将测量对OL-谱系的影响
使用各种转基因斑马鱼系的细胞,其允许发育中的OL和髓鞘形成的可视化。
我们将通过评估幼虫的行为来阐明这些变化的功能后果。另外我们
将使用一种方法来确定软骨藻酸对神经行为的发育暴露对以后生活的影响。
一组成熟的行为测定和表征成人中的基因表达模式
个脑袋在目标2中,我们将检验以下假设:发育期暴露于蛤蚌毒素(一种电压抑制剂)-
门控钠通道,靶向发育中的神经元,导致轴突生长缺陷。我们将可视化
运动神经元轴突生长的变化,并决定幼虫和成虫行为的功能变化。在
目的3,我们将检验早期暴露于低水平软骨藻酸和石房蛤毒素
靶向OL和神经元细胞,干扰活动依赖性髓鞘形成并导致增强的缺陷
在髓鞘形成和神经行为方面。我们还将测试软骨藻酸和石房蛤毒素可以导致
沉默的神经毒性,可以在以后的生活中被二次压力所掩盖。研究与合作
项目1和2以及社区外展核心将模拟人类接触以及它如何随着时间的推移而变化。
气候变化这项研究将确定神经行为效应的细胞和分子基础
在生命早期暴露于主要的HAB毒素之后,有助于了解潜在的长期-
软骨藻酸和石房蛤毒素对人类发育的长期健康影响,
评估与可能增加的这些毒素接触有关的公共健康风险。
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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Mark E Hahn其他文献
Mark E Hahn的其他文献
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{{ truncateString('Mark E Hahn', 18)}}的其他基金
Understanding the origins and mechanisms of aryl hydrocarbon receptor promiscuity
了解芳烃受体混杂的起源和机制
- 批准号:
10679532 - 财政年份:2023
- 资助金额:
$ 14.15万 - 项目类别:
Mechanisms Controlling Sensitivity and Resistance to Dioxin-like Compounds: Role of AIP
控制对二恶英类化合物的敏感性和耐受性的机制:AIP 的作用
- 批准号:
10538943 - 财政年份:2022
- 资助金额:
$ 14.15万 - 项目类别:
Gene-by-environment interactions that affect exposure-mediated congenital heart disease
影响暴露介导的先天性心脏病的基因与环境相互作用
- 批准号:
10216463 - 财政年份:2021
- 资助金额:
$ 14.15万 - 项目类别:
Gene-by-environment interactions that affect exposure-mediated congenital heart disease
影响暴露介导的先天性心脏病的基因与环境相互作用
- 批准号:
10655611 - 财政年份:2021
- 资助金额:
$ 14.15万 - 项目类别:
Project 3: Cellular and Molecular Mechanisms Underlying Long-term Effects of Early Life Exposure to HAB Toxins
项目 3:生命早期接触 HAB 毒素造成长期影响的细胞和分子机制
- 批准号:
10434783 - 财政年份:2018
- 资助金额:
$ 14.15万 - 项目类别:
Mechanisms of Embryo Response to Oxidative Stress
胚胎对氧化应激的反应机制
- 批准号:
8244524 - 财政年份:2009
- 资助金额:
$ 14.15万 - 项目类别:
Mechanisms of Embryo Response to Oxidative Stress
胚胎对氧化应激的反应机制
- 批准号:
8051862 - 财政年份:2009
- 资助金额:
$ 14.15万 - 项目类别:
Mechanisms of Embryo Response to Oxidative Stress
胚胎对氧化应激的反应机制
- 批准号:
8450175 - 财政年份:2009
- 资助金额:
$ 14.15万 - 项目类别:
Mechanisms of Embryo Response to Oxidative Stress
胚胎对氧化应激的反应机制
- 批准号:
7655110 - 财政年份:2009
- 资助金额:
$ 14.15万 - 项目类别:
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