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区域结构性脑损伤和认知障碍。慢性的
滥用酒精还与多种运动障碍有关。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、扑翼样震颤和
小脑功能障碍。虽然酒精引起的脑损伤可以通过酒精对神经的影响来解释
兴奋性或营养缺乏,我们尚未完全了解其分子和机制上的致病机制。
酒精发挥毒性并损害神经系统的细胞水平。线虫 秀丽隐杆线虫
是一种适合的模型生物,可用于剖析酒精的病理机制
神经毒性。我们对秀丽隐杆线虫的研究表明,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)可避免由以下原因引起的运动功能缺陷
长期接触酒精。此外,特异性诱导神经元特异性 UPRmt 的基因操作
激活足以防止酒精介导的运动障碍。我们假设
在选定的神经群体中激活 UPRmt 分支可以预防酒精性运动障碍。到
检验这一假设,我们提出两个具体目标:目标 1 将研究永久 UPRmt 如何防范
酒精介导的运动障碍;目标 2 将确定神经元 UPRmt 导致的机制
防止酒精介导的运动障碍。酒精介导的详细分析
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
导致有效的药物靶标,防止或改善酒精性运动障碍。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Hongkyun Kim其他文献
Hongkyun Kim的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Role of glucocorticoid receptor-mediated mRNA decay in alcohol dependence
糖皮质激素受体介导的 mRNA 衰减在酒精依赖中的作用
- 批准号:
10811212 - 财政年份:2023
- 资助金额:
$ 18.53万 - 项目类别:
6/11 Astrocyte-specific changes and interventions in alcohol dependence
6/11 星形胶质细胞特异性变化和酒精依赖干预
- 批准号:
10591606 - 财政年份:2022
- 资助金额:
$ 18.53万 - 项目类别:
An Investigation of Reward Processing in Co-occurring Alcohol Dependence and Loss of Control Eating
对同时发生的酒精依赖和饮食失控的奖励处理的研究
- 批准号:
486597 - 财政年份:2022
- 资助金额:
$ 18.53万 - 项目类别:
Studentship Programs
Identifying new targets for the treatment of alcohol dependence and relapse: epigenetic analysis of the abstinent brain
确定治疗酒精依赖和复发的新靶点:戒酒大脑的表观遗传学分析
- 批准号:
10396660 - 财政年份:2022
- 资助金额:
$ 18.53万 - 项目类别:
Identifying new targets for the treatment of alcohol dependence and relapse: epigenetic analysis of the abstinent brain
确定治疗酒精依赖和复发的新靶点:戒酒大脑的表观遗传学分析
- 批准号:
10553449 - 财政年份:2022
- 资助金额:
$ 18.53万 - 项目类别:
6/11 Astrocyte-specific changes and interventions in alcohol dependence
6/11 星形胶质细胞特异性变化和酒精依赖干预
- 批准号:
10409263 - 财政年份:2022
- 资助金额:
$ 18.53万 - 项目类别:
Novel GLT-1 activators for the treatment of alcohol dependence: preclinical studies
用于治疗酒精依赖的新型 GLT-1 激活剂:临床前研究
- 批准号:
10517529 - 财政年份:2022
- 资助金额:
$ 18.53万 - 项目类别:
Reducing alcohol-seeking behavior in a rat model of alcohol dependence
减少酒精依赖大鼠模型的寻酒行为
- 批准号:
10684236 - 财政年份:2022
- 资助金额:
$ 18.53万 - 项目类别:
Opposing Contributions of Oxytocin and Corticotropin-Release Factor to Alcohol Dependence
催产素和促肾上腺皮质激素释放因子对酒精依赖的相反作用
- 批准号:
10451814 - 财政年份:2021
- 资助金额:
$ 18.53万 - 项目类别:
Opposing Contributions of Oxytocin and Corticotropin-Release Factor to Alcohol Dependence
催产素和促肾上腺皮质激素释放因子对酒精依赖的相反作用
- 批准号:
10655413 - 财政年份:2021
- 资助金额:
$ 18.53万 - 项目类别:














{{item.name}}会员




