Subcellular-targeted CYP2E1 and alcohol in the brain
大脑中亚细胞靶向 CYP2E1 和酒精
基本信息
- 批准号:10496067
- 负责人:
- 金额:$ 35.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-20 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcetaldehydeAcuteAlcohol abuseAlcohol consumptionAlcohol dehydrogenaseAlcoholsBrainBrain regionCYP2E1 geneCaenorhabditis elegansCardiovascular DiseasesCell LineCellsCerebellumChronicConsumptionCultured CellsDiseaseEconomic BurdenEndoplasmic ReticulumEnzymesEthanolEthanol MetabolismEthanol toxicityExposure toFatty LiverFunding OpportunitiesGene TargetingGenotypeGoalsGrantHealthHeavy DrinkingHippocampusHumanIntakeLinkLipid PeroxidationMalignant NeoplasmsMeasuresMediatingMembraneMetabolicMetabolic dysfunctionMetabolismMicrosomesMitochondriaMusMyopathyNervous System TraumaNeurosciencesOrganOrganellesOsteoporosisOutcomeOxidative StressOxidative Stress InductionPathologyPathway interactionsPrefrontal CortexProductionRegulationResearchResearch PersonnelResourcesRoleSpecificityStressSystemTestingTherapeuticToxic effectTransgenic MiceTransgenic ModelTransgenic OrganismsUnited StatesWorkalcohol effectalcohol exposurealcohol use disorderbinge drinkingcatalasechronic alcohol ingestionexperimental studyfrontal lobeinnovationinsightliver injurymitochondrial dysfunctionmitochondrial metabolismnervous system disorderperoxisomepreventpreventable deathprotein complexrespiratorysubcellular targetingtherapeutic target
项目摘要
PROJECT SUMMARY
Metabolism of alcohol (i.e., ethanol) to acetaldehyde within different brain regions and in different subcellular
compartments, and how that metabolism changes with chronic ethanol use, is not well-understood. The long-
term goal is to identify adaptive changes that occur in chronic ethanol abuse and to identify therapeutic
strategies to prevent or reverse neurological damage from ethanol. The objective of this proposal is to
determine subcellular regulation of ethanol metabolism in mitochondria and endoplasmic reticulum (ER) by
CYP2E1 during acute and chronic ethanol use, and to determine the consequences of the differential targeting.
The central hypothesis is that targeting of CYP2E1 to mitochondria will be increased during chronic alcohol use
in some regions of the brain that are sensitive to ethanol-induced damage, and that high mitochondrial
targeting will drive high mitochondrial acetaldehyde production and resulting mitochondrial dysfunction and
oxidative stress. The rationale underlying this hypothesis is that CYP2E1 expression overall is increased in
brain regions that are sensitive to ethanol, including the prefrontal cortex, hippocampus, and cerebellum, and
these regions also develop mitochondrial dysfunction and oxidative stress during ethanol use. The central
hypothesis will be tested by pursuing three specific aims: 1) Evaluate subcellular specificity of induction of
CYP2E1 by acute and chronic ethanol in the brain; 2) Determine the role of mitochondria- and ER-targeted
CYP2E1 in mitochondrial effects of chronic ethanol use; and 3) Measure contribution of mitochondria- and ER-
localized CYP2E1 to ethanol-induced oxidative stress. We will pursue these aims using an innovative strategy
of three complementary systems: mice, C. elegans, and cultured cells. In each system we have a null
background lacking CYP2E1, a wild-type CYP2E1 gene targeted to both mitochondria and ER, an ER-targeted
CYP2E1, and a mitochondrial-targeted CYP2E1. The proposed research is significant because it will elucidate
how ethanol metabolism by CYP2E1 changes over a chronic ethanol use paradigm, and could reveal
mitochondrial CYP2E1 as a liability for ethanol toxicity. It is also significant because it generates useful
platforms for studying subcellular localization-dependent effects of CYP2E1. The work will develop
foundational resources that will be used by other researchers. The proximate expected outcome of this work is
an understanding of how CYP2E1 contributes to the effects of ethanol in the brain during chronic and acute
binge drinking. The results will have an important positive impact immediately because they will establish
better understanding of the relationship between ethanol metabolism in brain regions with toxicity, and in the
long-term because they lay the groundwork for identifying therapeutic opportunities.
项目摘要
酒精代谢(即,乙醇)在不同脑区和不同亚细胞中转化为乙醛。
然而,对于乙醇的代谢以及代谢如何随着慢性乙醇使用而变化,目前还没有很好的了解。很长的-
长期目标是确定慢性乙醇滥用中发生的适应性变化,
预防或逆转乙醇引起的神经损伤的策略。这项建议的目的是
确定线粒体和内质网(ER)中乙醇代谢的亚细胞调节,
CYP 2 E1在急性和慢性乙醇使用,并确定差异靶向的后果。
中心假设是,慢性饮酒会增加CYP 2 E1对线粒体的靶向作用
在大脑的某些区域,对乙醇诱导的损伤敏感,
靶向将驱动高线粒体乙醛产生和导致的线粒体功能障碍,
氧化应激这一假设的基本原理是,CYP 2 E1表达总体上增加,
对乙醇敏感的大脑区域,包括前额叶皮层、海马和小脑,以及
这些区域在使用乙醇期间也发生线粒体功能障碍和氧化应激。中央
将通过追求三个具体目标来测试假设:1)评估诱导的亚细胞特异性,
CYP 2 E1通过急性和慢性乙醇在大脑中的作用; 2)确定线粒体和ER靶向的作用
CYP 2 E1在慢性乙醇使用的线粒体效应中的作用;以及3)测量线粒体和ER-1的贡献。
将CYP 2 E1定位于乙醇诱导的氧化应激。我们将采用创新战略实现这些目标
三个互补系统:小鼠,C.以及培养的细胞。在每个系统中,我们都有一个null
背景缺乏CYP 2 E1,一种靶向线粒体和ER的野生型CYP 2 E1基因,
CYP 2 E1,以及一种靶向于尿道的CYP 2 E1。这项研究很重要,因为它将阐明
CYP 2 E1的乙醇代谢如何在慢性乙醇使用模式中发生变化,并可能揭示
线粒体CYP 2 E1作为乙醇毒性的责任。它也很重要,因为它产生了有用的
研究CYP 2 E1的亚细胞定位依赖性作用的平台。这项工作将发展
其他研究人员将使用的基础资源。这项工作的最接近的预期成果是
了解CYP 2 E1如何在慢性和急性期间对乙醇在大脑中的影响做出贡献
酗酒结果将立即产生重要的积极影响,因为它们将建立
更好地了解酒精代谢在大脑区域与毒性之间的关系,
因为它们为确定治疗机会奠定了基础。
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
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:
$ 35.45万 - 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:
$ 35.45万 - 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:
$ 35.45万 - 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:
$ 35.45万 - 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:
$ 35.45万 - 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:
$ 35.45万 - 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:
$ 35.45万 - 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:
9189444 - 财政年份:2016
- 资助金额:
$ 35.45万 - 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:
$ 35.45万 - 项目类别:
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