The role of mitochondrial stress response in alcohol-mediated neurotoxicity
线粒体应激反应在酒精介导的神经毒性中的作用
基本信息
- 批准号:10708781
- 负责人:
- 金额:$ 18.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-25 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Alcohol consumptionAlcohol dependenceAlcoholsBrain InjuriesCaenorhabditis elegansCell DeathCellular StressCerebellar DiseasesChronicCognition DisordersCytoplasmDataDevelopmentEthanol toxicityExhibitsFunctional disorderGenesGeneticGenetic ModelsGenetic studyHealthHepatic EncephalopathyHomologous GeneHumanImpaired cognitionImpairmentInsulin-Like Growth Factor ReceptorInvestigationLipidsMalnutritionMammalsMediatingMitochondriaMolecularMotorMovementMovement DisordersNematodaNervous SystemNervous System TraumaNeuronsNeurosecretory SystemsNutritionalOxidative Stress InductionPathogenicityPathologicPathway interactionsPeripheralPopulationProteinsRoleSignal InductionSignal PathwaySignal TransductionTestingTherapeuticThiamine DeficiencyTimeTissuesToxic effectTremoralcohol consequencesalcohol effectalcohol exposurealcohol misusealcohol use disorderbiological adaptation to stresschronic alcohol ingestiondruggable targetgenetic analysisgenetic manipulationmitochondrial dysfunctionmodel organismmotor impairmentneuralneurotoxicityneurotransmissionproblem drinkerproteostasisresponsetranscription factor
项目摘要
Chronic, excessive alcohol use causes regional structural brain damage and cognitive disorders. Chronic
alcohol misuse is also associated with a wide array of movement impairments. Chronic alcohol consumption
alone, or together with alcoholic hepatic encephalopathy, can cause various types of tremor, asterixis, and
cerebellar dysfunction. While alcohol-induced brain damage has been explained by alcohol’s effects on neural
excitability or nutritional deficiency, we do not fully understand the pathogenic mechanism at the molecular and
cellular levels by which alcohol exerts its toxicity and damages the nervous system. The nematode C. elegans
is an amenable model organism that can be used for dissecting the pathological mechanism of alcoholic
neurotoxicity. Our study in C. elegans shows that while alcohol strongly induces many conserved cellular
stress responses, its main toxic effects are centered on mitochondrial function. Remarkably, we find that
perpetual mitochondrial unfolded protein response (UPRmt) spares from a motor function deficit caused by
chronic alcohol exposure. Moreover, a genetic manipulation that specifically induces neuron-specific UPRmt
activation is sufficient to protect against alcohol-mediated movement impairment. We hypothesize that
activation of a branch of UPRmt in a select neural population protects against alcoholic movement disorders. To
test this hypothesis, we propose two specific aims: aim 1 will investigate how perpetual UPRmt protects against
alcohol-mediated movement impairment; and aim 2 will identify the mechanism by which neuronal UPRmt leads
to the protection against alcohol-mediated movement impairment. A detailed analysis of alcohol-mediated
UPRmt and its intra- and intercellular signaling in the context of alcohol-mediated movement impairment will
lead to effective druggable targets that protect against, or ameliorate, alcoholic movement impairment.
长期过量饮酒会导致局部结构性脑损伤和认知障碍。慢性
酒精滥用还与各种各样的行动障碍有关。长期饮酒
单独或与酒精性肝性脑病一起,可引起各种类型的震颤、震颤,
小脑功能障碍虽然酒精引起的脑损伤已经被解释为酒精对神经系统的影响,
兴奋性或营养缺乏,我们不完全了解致病机制的分子和
酒精通过细胞水平发挥其毒性并损害神经系统。线虫C. elegans
是一个顺从的模式生物,可用于解剖酒精的病理机制,
神经毒性我们在C. elegans表明,虽然酒精强烈诱导许多保守的细胞,
应激反应,其主要毒性作用集中在线粒体功能上。值得注意的是,我们发现,
永久性线粒体未折叠蛋白反应(UPRmt)避免了运动功能缺陷,
慢性酒精暴露此外,特异性诱导神经元特异性UPRmt
激活足以防止酒精介导的运动损伤。我们假设
在选定的神经群中激活UPRmt的分支可防止酒精性运动障碍。到
为了验证这一假设,我们提出了两个具体目标:目标1将研究永久性UPRmt如何防止
酒精介导的运动障碍;目标2将确定神经元UPRmt导致运动障碍的机制。
对酒精介导的运动障碍的保护。详细分析了酒精介导的
在酒精介导的运动障碍的背景下,UPRmt及其细胞内和细胞间信号传导将
导致有效的可药物化的靶点,其防止或改善酒精性运动损伤。
项目成果
期刊论文数量(0)
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Hongkyun Kim其他文献
Hongkyun Kim的其他文献
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{{ truncateString('Hongkyun Kim', 18)}}的其他基金
The role of mitochondrial stress response in alcohol-mediated neurotoxicity
线粒体应激反应在酒精介导的神经毒性中的作用
- 批准号:
10452854 - 财政年份:2022
- 资助金额:
$ 18.53万 - 项目类别:
Identification of genes responsible for sarcolemmal integrity in C. elegans
鉴定负责线虫肌膜完整性的基因
- 批准号:
8463045 - 财政年份:2012
- 资助金额:
$ 18.53万 - 项目类别:
Identification of genes responsible for sarcolemmal integrity in C. elegans
鉴定负责线虫肌膜完整性的基因
- 批准号:
8386003 - 财政年份:2012
- 资助金额:
$ 18.53万 - 项目类别:
Identification of Novel Components of the Dystrophin Complex Using C. Elegans
使用线虫鉴定抗肌营养不良蛋白复合物的新成分
- 批准号:
7372709 - 财政年份:2007
- 资助金额:
$ 18.53万 - 项目类别:
Identification of Novel Components of the Dystrophin Complex Using C. Elegans
使用线虫鉴定肌营养不良蛋白复合物的新成分
- 批准号:
7501975 - 财政年份:2007
- 资助金额:
$ 18.53万 - 项目类别:
Identification of Novel Components of the Dystrophin Complex Using C. Elegans
使用线虫鉴定肌营养不良蛋白复合物的新成分
- 批准号:
7749609 - 财政年份:2007
- 资助金额:
$ 18.53万 - 项目类别:
Identification of Novel Components of the Dystrophin Complex Using C. Elegans
使用线虫鉴定肌营养不良蛋白复合物的新成分
- 批准号:
7802946 - 财政年份:2007
- 资助金额:
$ 18.53万 - 项目类别:
Identification of Novel Components of the Dystrophin Complex Using C. Elegans
使用线虫鉴定肌营养不良蛋白复合物的新成分
- 批准号:
7596932 - 财政年份:2007
- 资助金额:
$ 18.53万 - 项目类别:
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