Molecular Mechanisms of Marine Organohalogen Bioaccumulation and Neurotoxicity
海洋有机卤素生物累积和神经毒性的分子机制
基本信息
- 批准号:10172906
- 负责人:
- 金额:$ 11.76万
- 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:2018-09-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:ABCB1 geneABCG2 geneAddressBenefits and RisksBindingBlood - brain barrier anatomyBrainCRISPR/Cas technologyCa(2+)-Transporting ATPaseCardiovascular systemCellsChemicalsComplexConsumptionCrystallizationDataDevelopmentEcosystemElectrophysiology (science)EnvironmentEnvironmental HealthEtiologyExposure toFemaleFishesFluorescenceFutureGenderGenesGoalsHealthHeat Stress DisordersHippocampus (Brain)HumanImmuneImmune systemIn VitroInfrastructureIntestinesKidneyKnowledgeLightLinkLiverMediatingMissionModelingMolecularMolecular TargetMorphologyMulti-Drug ResistanceMutationMyopathyNational Institute of Environmental Health SciencesNervous system structureNeurologicNeuronsNeurotoxinsOceansOutcomePathway interactionsPenetrationPharmaceutical PreparationsPhysiologicalPhysiologyPolychlorinated BiphenylsPopulationProcessProtein IsoformsPublic HealthRelative RisksReticulumRiskRoleRyR1RyanodineRyanodine ReceptorsSalmonSea UrchinsSeafoodSiteStructureStructure-Activity RelationshipTestingTimeTissuesToxic effectTunaUnited StatesUp-RegulationWild Type MouseWorkXenobioticsanthropogenesisbioaccumulationcancer cellcancer typecellular imagingdeep oceanexposed human populationinhibitor/antagonistmalemanmuscular systemneurotoxicitypersistent organic pollutantspollutantpollutant interactionreceptorrisk minimizationscreeningsexuptakevoltage clamp
项目摘要
ABSTRACT
There is urgent public health need to better understand the relative risks and benefits associated with
consumption of seafood. The overall mission of this project is to understand the toxicity of marine organohalogen
pollutants. We take a powerful approach to understanding and mitigating this risk by asking two questions, central
to future efforts to predict and minimize risk. Aim 1 of this project asks how these compounds bioaccumulate,
focusing on xenobiotic transporters, which are a key pathway for limiting accumulation of foreign chemicals. We
will determine the interactions of the four major human xenobiotic transporters (XTs) with environmentally
relevant natural and man-made marine organohalogens. The results will extend and expand the scope of our
previous work indicating that several of these compounds can act as potent inhibitors of transporter function. In
parallel, we will take advantage of recent progress with heterologous transporter-expression and CRISPR/CAS9
gene editing in sea urchins, to dissect the functional role of XTs in governing bioaccumulation in marine cells.
This will be supported by a structure guided approach to determine how evolutionary changes in transporter
structure modify interactions with TICs, following up on recent progress towards purification and crystallization
of marine XTs in complex with pollutants. Aim 2 of this project will determine the structure activity relationships
governing neurotoxicity of marine pollutants. These studies are motivated by preliminary data indicating that
naturally produced organohalogens are highly potent inhibitors of ryanodine sensitive Ca2+ channels (RyRs) and
Ca2+ ATPase transporters (SERCAs), which are arguably the most direct targets of environmentally relevant
organohalogens in the brain. We will use primary cultures of hippocampal neurons cultured from male and female
wild type mice to determine how activity at these molecular targets alter neuronal network Ca2+ dynamics and
morphology using real-time fluorescence cell imaging and morphometric approaches. In addition, we will determine
how hippocampal neurons that express mutation RyR1-R163C known to confer heat stress intolerance, alter
sensitivity to organohalogens, and ask whether these effects are gender-specific. These studies will address the
critical need to better understand the molecular mechanisms by which naturally occurring and man-made seafood
pollutants accumulate in target cells and perturb the Ca2+ dynamics essential for normal neuronal network
development.
摘要
公共卫生迫切需要更好地了解与之相关的相对风险和好处
食用海鲜。这个项目的总体任务是了解海洋有机卤素的毒性。
污染物。我们采取了一种强有力的方法来理解和缓解这种风险,方法是问两个问题,中心
为未来预测和最大限度地减少风险所做的努力。这个项目的目标1是问这些化合物是如何生物积累的,
重点关注异种生物转运体,这是限制外来化学品积累的关键途径。我们
将决定四种主要的人类异种生物转运蛋白(XTS)与环境的相互作用
相关的天然和人造海洋有机卤素。这一成果将扩大和扩大我们的
先前的工作表明,这些化合物中的几个可以作为转运蛋白功能的有效抑制剂。在……里面
同时,我们将利用异源转运蛋白表达和CRISPR/Cas9的最新进展
海胆中的基因编辑,剖析XTS在调控海洋细胞生物积累中的功能作用。
这将得到结构指导方法的支持,以确定转运体的进化变化
结构修饰与TIC的相互作用,跟踪纯化和结晶的最新进展
海洋XTS与污染物的复合体。本项目的目标2将确定结构活动关系
管理海洋污染物的神经毒性。这些研究的动机是初步数据表明
天然产生的有机卤素是兰诺定敏感的钙通道(RyRs)和
CA2+ATPase转运体(SERCA),可以说是与环境相关的最直接的靶标
大脑中的有机卤素。我们将使用原代培养的雄性和雌性海马神经元
野生型小鼠以确定这些分子靶点的活动如何改变神经元网络钙动力学和
使用实时荧光细胞成像和形态计量学方法的形态学。此外,我们将确定
表达突变RyR1-R163C的海马神经元如何改变已知的热应激耐受
对有机卤素的敏感性,并询问这些影响是否因性别而异。这些研究将针对
迫切需要更好地了解天然海鲜和人造海鲜的分子机制
污染物在靶细胞中积累并扰乱正常神经网络所必需的钙动力学
发展。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
AMRO M HAMDOUN其他文献
AMRO M HAMDOUN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('AMRO M HAMDOUN', 18)}}的其他基金
Development of foundational building blocks for stable genetic modification of sea urchin embryos
开发海胆胚胎稳定遗传修饰的基础构件
- 批准号:
10575685 - 财政年份:2022
- 资助金额:
$ 11.76万 - 项目类别:
Molecular Mechanisms of Marine Organohalogen Bioaccumulation and Neurotoxicity
海洋有机卤素生物累积和神经毒性的分子机制
- 批准号:
10438597 - 财政年份:2018
- 资助金额:
$ 11.76万 - 项目类别:
CONTROL OF ULTIDRUG EFFLUX TRANSPORTER ACTIVITY BY CELL SURFACE REORGANIZATION
通过细胞表面重组控制超级药物外排转运蛋白活性
- 批准号:
8169651 - 财政年份:2010
- 资助金额:
$ 11.76万 - 项目类别:
Control of Multidrug Transport Activity in Embryos
胚胎中多药物转运活性的控制
- 批准号:
8126178 - 财政年份:2009
- 资助金额:
$ 11.76万 - 项目类别:
Control of Multidrug Transport Activity in Embryos
胚胎中多药物转运活性的控制
- 批准号:
7932788 - 财政年份:2009
- 资助金额:
$ 11.76万 - 项目类别:
Control of Multidrug Transport Activity in Embryos
胚胎中多药物转运活性的控制
- 批准号:
7810286 - 财政年份:2009
- 资助金额:
$ 11.76万 - 项目类别:
Control of efflux transporter activity by cell surface reorganization in embryos.
通过胚胎细胞表面重组控制外排转运蛋白活性。
- 批准号:
7620867 - 财政年份:2008
- 资助金额:
$ 11.76万 - 项目类别:
Control of efflux transporter activity by cell surface reorganization in embryos.
通过胚胎细胞表面重组控制外排转运蛋白活性。
- 批准号:
7450001 - 财政年份:2008
- 资助金额:
$ 11.76万 - 项目类别:
Initiation of Multidrug Transport at Fertilization.
受精时多药物转运的启动。
- 批准号:
7150607 - 财政年份:2005
- 资助金额:
$ 11.76万 - 项目类别:
Initiation of Multidrug Transport at Fertilization.
受精时多药物转运的启动。
- 批准号:
6884533 - 财政年份:2005
- 资助金额:
$ 11.76万 - 项目类别:














{{item.name}}会员




