Role of Mitochondrial CYP2E1 in Chemical Exposure-Driven Neurodegeneration
线粒体 CYP2E1 在化学品暴露驱动的神经变性中的作用
基本信息
- 批准号:9189444
- 负责人:
- 金额:$ 5.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-01 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgeBiological AssayBullaCYP2E1 geneCaenorhabditis elegansCell DeathCellsCessation of lifeChemical ExposureClinicalDevelopmentDisease ProgressionEarly DiagnosisEndoplasmic ReticulumEnvironmentEnvironmental PollutantsEnvironmental Risk FactorExposure toFellowshipFluorescence MicroscopyFunctional disorderGeneticGenetic RiskGenus HippocampusGoalsHealthHepatocyteHumanIn SituInterventionKnowledgeLeadLifeLinkLiverLongevityMeasurementMeasuresMembrane PotentialsMetabolic ActivationMetabolismMethanolMitochondriaMitochondrial DNAMitochondrial ProteinsModelingMutationNematodaNerve DegenerationNeurodegenerative DisordersNeuronsOrganellesPC12 CellsParkinson DiseasePathogenesisPersonsPesticidesPharmaceutical PreparationsPlayPopulationPreventive measureResearchRespirationRisk AssessmentRisk FactorsRoleSolventsSubstantia nigra structureSymptomsTestingToxic Environmental SubstancesToxic effectToxicant exposureTransgenic OrganismsTrichloroethyleneUnited States National Institutes of HealthWhole Organismabstractingbasecell injurydopaminergic neuronimprovedin vivoinstrumentmitochondrial dysfunctionmitochondrial membranenervous system disorderneuron lossneuroprotectionparkin gene/proteinprophylacticresearch studyrespiratory proteinsmall moleculetargeted treatmenttherapeutic targettoxicant
项目摘要
Project Summary/Abstract
Parkinson's Disease (PD) is one of the most common neurodegenerative disorders, affecting >1% of the
population over age 60. PD pathophysiology includes preferential loss of dopaminergic neurons in the
substantia nigra (SN), and has been linked to both genetic and environmental risk factors. However, genetics
can only explain 5-10% of late-onset cases, so environment may play a larger role in most cases. PD has been
demonstrated at the cellular level to involve mitochondrial dysfunction. Multiple environmental toxicants known
to be toxic to mitochondria require metabolic activation to exert this toxicity through reactive metabolites that
damage vulnerable mitochondrial proteins and DNA. Two well-known examples of metabolically activated
compounds are trichloroethylene, a pervasive environmental pollutant, and methanol, a common solvent and
fuel additive; both trichloroethylene and methanol are activated by cytochrome P450 2E1 (CYP2E1). CYP2E1
has traditionally been studied in the endoplasmic reticulum (ER) of liver hepatocytes; however, it is also
expressed in SN dopaminergic neurons. Moreover, CYP2E1 is bimodally targeted to ER and mitochondria in
those cells. Relatively little is known about the consequence of mitochondrial CYP2E1 localization on
mitochondrial integrity and/or function and ultimately pathogenesis of neurodegenerative diseases.
This NIH postdoctoral fellowship proposal will assess the role of mitochondrial CYP2E1 (mtCYP2E1) in
mitochondrial dysfunction and neurodegeneration due to the activation of trichloroethylene and methanol in
transgenic human CYP2E1-expressing PC-12 cells and C. elegans (in vivo). We hypothesize that activation
of these toxicants by CYP2E1 within mitochondrial organelles will cause localized damage that triggers
mitochondrial dysfunction and drives neurodegeneration. To test this hypothesis, mitochondrial
dysfunction will be assessed in cells and in vivo through a battery of mitochondrial assays including whole-cell
and whole-organism respiration assays using a Seahorse XF instrument, ATP measurements, and
assessment of mitochondrial membrane potential. Neurodegeneration induced by methanol and
trichloroethylene will be assessed in vivo by fluorescence microscopy of live C. elegans nematodes bearing
GFP-tagged neurons. Overall, knowledge gained from this study will aid in development of more accurate risk
assessments for neurodegeneration triggered by exposures to environmental toxicants and could provide new
targets for intervention and/or neuroprotection. The following aims will be pursued:
Specific Aim 1: Determine CYP2E1-dependent mitochondrial dysfunction induced by toxicants.
Specific Aim 2: Assess the role of mitochondrial CYP2E1 in toxicant-induced neurodegeneration.
项目总结/摘要
帕金森病(PD)是最常见的神经退行性疾病之一,影响>1%的帕金森病患者。
60岁以上人口。PD的病理生理学包括帕金森氏病中多巴胺能神经元的优先损失。
黑质(SN),并与遗传和环境风险因素有关。然而,遗传学
仅能解释5-10%的迟发性病例,因此环境在大多数病例中可能起更大的作用。PD已经
在细胞水平上证明涉及线粒体功能障碍。已知多种环境毒物
对线粒体有毒需要代谢活化以通过反应性代谢物发挥这种毒性,
破坏脆弱的线粒体蛋白质和DNA。两个众所周知的代谢活化的例子
化合物是三氯乙烯,一种普遍的环境污染物,和甲醇,一种常见的溶剂,
燃料添加剂;三氯乙烯和甲醇都被细胞色素P450 2 E1(CYP 2 E1)激活。CYP2E1
传统上在肝细胞的内质网(ER)中进行了研究;然而,
在SN多巴胺能神经元中表达。此外,CYP 2 E1是双峰靶向ER和线粒体,
这些细胞。关于线粒体CYP 2 E1定位对细胞凋亡的影响知之甚少。
线粒体完整性和/或功能以及最终神经变性疾病的发病机制。
这项NIH博士后奖学金提案将评估线粒体CYP 2 E1(mtCYP 2 E1)在以下方面的作用:
由于三氯乙烯和甲醇的激活而导致线粒体功能障碍和神经退行性变
转基因人CYP 2 E1表达PC-12细胞和C. elegans(in vivo).我们假设激活
CYP 2 E1在线粒体细胞器内对这些毒物的毒性会引起局部损伤,
线粒体功能障碍和驱动神经变性。为了验证这一假设,
将通过一系列线粒体测定,包括全细胞测定,
和使用Seahorse XF仪器的全生物体呼吸测定,ATP测量,以及
线粒体膜电位的评估。甲醇诱导的神经变性和
三氯乙烯将通过活C的荧光显微镜在体内进行评估。线虫性线虫
GFP标记的神经元。总体而言,从本研究中获得的知识将有助于开发更准确的风险
评估暴露于环境毒物引发的神经变性,并可能提供新的
用于干预和/或神经保护的靶点。将努力实现以下目标:
具体目的1:确定毒物诱导的CYP 2 E1依赖性线粒体功能障碍。
具体目标2:评估线粒体CYP 2 E1在毒物诱导的神经变性中的作用。
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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Jessica Helene Hartman其他文献
Jessica Helene Hartman的其他文献
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{{ truncateString('Jessica Helene Hartman', 18)}}的其他基金
Subcellular-targeted CYP2E1 and alcohol in the brain
大脑中亚细胞靶向 CYP2E1 和酒精
- 批准号:
10496067 - 财政年份:2023
- 资助金额:
$ 5.25万 - 项目类别:
Regulation and Consequences of Cytochrome P450 2E1
细胞色素 P450 2E1 的调节和后果
- 批准号:
10713697 - 财政年份:2023
- 资助金额:
$ 5.25万 - 项目类别:
Exercise, MANF, and Chemical-Induced Neurodegeneration
运动、MANF 和化学物质引起的神经变性
- 批准号:
10380263 - 财政年份:2021
- 资助金额:
$ 5.25万 - 项目类别:
Exercise, MANF, and Chemical-Induced Neurodegeneration
运动、MANF 和化学物质引起的神经变性
- 批准号:
10307629 - 财政年份:2020
- 资助金额:
$ 5.25万 - 项目类别:
Exercise, MANF, and Chemical-Induced Neurodegeneration
运动、MANF 和化学物质引起的神经变性
- 批准号:
10513154 - 财政年份:2020
- 资助金额:
$ 5.25万 - 项目类别:
Exercise, MANF, and Chemical-Induced Neurodegeneration
运动、MANF 和化学物质引起的神经变性
- 批准号:
10513823 - 财政年份:2020
- 资助金额:
$ 5.25万 - 项目类别:
Exercise, MANF, and Chemical-Induced Neurodegeneration
运动、MANF 和化学物质引起的神经变性
- 批准号:
10217454 - 财政年份:2020
- 资助金额:
$ 5.25万 - 项目类别:
Exercise, MANF, and chemical-induced neurodegeneration
运动、MANF 和化学物质引起的神经变性
- 批准号:
10020404 - 财政年份:2019
- 资助金额:
$ 5.25万 - 项目类别:
Role of Mitochondrial CYP2E1 in Chemical Exposure-Driven Neurodegeneration
线粒体 CYP2E1 在化学品暴露驱动的神经变性中的作用
- 批准号:
9319548 - 财政年份:2016
- 资助金额:
$ 5.25万 - 项目类别:
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