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脑部结构损伤和认知障碍。慢性
酒精滥用还与一系列运动障碍有关。慢性饮酒
单独或与酒精性肝性脑病一起,可引起各种类型的震颤、星状突起和
小脑功能障碍。虽然酒精引起的脑损伤是通过酒精对神经的影响来解释的
兴奋性或营养缺乏,我们还没有完全从分子和分子水平上了解其发病机制。
酒精产生毒性并损害神经系统的细胞水平。线虫线虫
是一种可用于剖析酒精中毒病理机制的可服从模式生物。
神经毒性。我们对线虫的研究表明,虽然酒精强烈地诱导了许多保守的细胞
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)可避免由以下原因引起的运动功能缺陷
长期酗酒。此外,一种特异地诱导神经元特异性UPRmt的基因操作
激活足以保护身体免受酒精引起的运动损伤。我们假设
在选定的神经群体中激活UPRmt的一个分支可以预防酒精运动障碍。至
检验这一假设,我们提出了两个具体目标:目标1将调查永久UPRmt如何预防
酒精介导的运动障碍;目标2将确定神经元UPRmt的领导机制
对酒精引起的运动损伤的保护。酒精介体的详细分析
UPRmt及其在酒精介导的运动障碍背景下的细胞内和细胞间信号转导将
导致有效的可用药靶点,防止或改善酒精运动障碍。
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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