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结构损伤和认知障碍。慢性
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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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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