Ethanol Hepatotoxicity and NO-Dependent Mitochondrial Dysfunction
乙醇肝毒性和 NO 依赖性线粒体功能障碍
基本信息
- 批准号:7535033
- 负责人:
- 金额:$ 29.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-03-05 至 2011-11-30
- 项目状态:已结题
- 来源:
- 关键词:Alcohol HepatotoxicityAlcohol dependenceAlcoholismAlcoholsAnimal FeedAntioxidantsCellsChronicDataDevelopmentDietEthanolEthanol dependenceFunctional disorderFundingHepaticHepatotoxicityHumanHypoxiaIndiumLeadLiverMeasurementMitochondriaMitochondrial DNAMitochondrial ProteinsModelingModificationMusNitric OxideNitric Oxide SynthaseNitrogenOxygenPharmaceutical PreparationsPost-Translational Protein ProcessingProtein IsoformsProteomeProteomicsPublic HealthRattusResearch PersonnelRespirationRespiratory ChainRoleTestingTherapeutic UsesToxic effectadenylate kinasealcohol abuse therapyalcohol exposurealcohol responsechronic alcohol ingestionhuman NOS2A proteininflammatory markerinhibitor/antagonistmitochondrial dysfunctionnovelnovel strategiespreventprogramsresearch studyresponse
项目摘要
Increased hypoxia in response to ethanol contributes to hepatotoxicity through mechanisms that are
not understood in detail. Mitochondria! dysfunction and the associated formation of reactive oxygen
and nitrogen species (ROS/RNS) appear to be a consequence of alcohol exposure in the liver. We
hypothesized that ethanol-dependent hypoxia involved a contribution from the nitric oxide (NO)
interaction with the mitochondrial respiratory chain, and this has been supported by studies
undertaken in the previous funding period. In this competing renewal, we build upon these findings
that demonstrate a) enhanced sensitivity to the NO-dependent inhibition of mitochondrial respiration
occurs early on exposure to alcohol b) this response is ablated in mice lacking the inducible NO
synthase isoform c) these changes are associated with changes in the mitochondrial proteome and
oxidative modification of proteins and mitochondrial DNA. These data have led to the hypothesis
that alcohol hepatotoxicity is exacerbated through increased mitochondrial dysfunction and
these effects will be ameliorated by mitochondrially targeted antioxidants. This concept will
be tested by pursuit of the following Specific Aims: 1. Determine the effect of mitochondrially
targeted antioxidants (MTA) on the development of alcohol-dependent hepatoxicity and hypoxia. 2:
Determine the effects of MTA on the chronic alcohol-dependent changes in activity of mitochondrial
proteins, sensitivity to inhibition of the respiratory chain by NO and damage to mtDNA. 3: Determine
the effects of MTA on the ethanol dependent modifications of the mitochondrial proteome. This
project will contribute to public health through defining the mechanisms that lead to the liver
damage that occurs in response to chronic alcoholism. In addition, the possibility of using a new
class of drugs directed to the parts of the cell that produce energy to reverse or prevent these toxic
effects of alcohol will be tested.
乙醇引起的缺氧增加通过以下机制导致肝毒性:
没有详细了解。线粒体!功能障碍和相关的活性氧形成
和氮物质(ROS/RNS)似乎是肝脏中酒精暴露的结果。我们
假设乙醇依赖性缺氧涉及一氧化氮(NO)的贡献,
与线粒体呼吸链的相互作用,这已经得到了研究的支持
上一个供资期。在这场竞争性的更新中,我们以这些发现为基础,
其证明a)对线粒体呼吸的NO依赖性抑制的敏感性增强
B)在暴露于酒精的早期发生,这种反应在缺乏诱导型NO的小鼠中被消除
合酶同种型c)这些变化与线粒体蛋白质组的变化相关,
蛋白质和线粒体DNA的氧化修饰。这些数据导致了一种假设
酒精肝毒性通过增加线粒体功能障碍而加剧,
这些作用将通过靶向前列腺的抗氧化剂来改善。这个概念将
通过追求以下具体目标进行测试:1。确定药物的效果
靶向抗氧化剂(MTA)对酒精依赖性肝毒性和缺氧的发展。第二章:
确定MTA对慢性酒精依赖性线粒体活性变化的影响
蛋白质,对NO抑制呼吸链的敏感性和对mtDNA的损伤。3:确定
MTA对线粒体蛋白质组的乙醇依赖性修饰的影响。这
该项目将通过定义导致肝脏的机制,
慢性酒精中毒引起的损伤。此外,使用新的
一类药物针对细胞中产生能量以逆转或预防这些有毒物质的部分
酒精的影响将被测试。
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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VICTOR M DARLEY-USMAR其他文献
VICTOR M DARLEY-USMAR的其他文献
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{{ truncateString('VICTOR M DARLEY-USMAR', 18)}}的其他基金
Core D: Comparative Mitochondrial Health Assessment Core
核心 D:比较线粒体健康评估核心
- 批准号:
8958641 - 财政年份:2015
- 资助金额:
$ 29.46万 - 项目类别:
Translational Bioenergetics in Patients with Alcoholic Liver Disease
酒精性肝病患者的转化生物能学
- 批准号:
8887823 - 财政年份:2015
- 资助金额:
$ 29.46万 - 项目类别:
Translational Bioenergetics in Patients with Alcoholic Liver Disease
酒精性肝病患者的转化生物能学
- 批准号:
9061506 - 财政年份:2015
- 资助金额:
$ 29.46万 - 项目类别:
Mitochondrial Bioenergetic Dysfunction and Chlorine Toxicity
线粒体生物能功能障碍和氯毒性
- 批准号:
8740480 - 财政年份:2013
- 资助金额:
$ 29.46万 - 项目类别:
Mitochondrial Bioenergetic Dysfunction and Chlorine Toxicity
线粒体生物能功能障碍和氯毒性
- 批准号:
8608361 - 财政年份:2013
- 资助金额:
$ 29.46万 - 项目类别:
Mitochondrial Haplotype Influences LV Dysfunction in Heart Failure
线粒体单倍型影响心力衰竭中的左心室功能障碍
- 批准号:
8458082 - 财政年份:2012
- 资助金额:
$ 29.46万 - 项目类别:
Mitochondrial Haplotype Influences LV Dysfunction in Heart Failure
线粒体单倍型影响心力衰竭中的左心室功能障碍
- 批准号:
8645719 - 财政年份:2012
- 资助金额:
$ 29.46万 - 项目类别:
Mitochondrial Haplotype Influences LV Dysfunction in Heart Failure
线粒体单倍型影响心力衰竭中的左心室功能障碍
- 批准号:
8826620 - 财政年份:2012
- 资助金额:
$ 29.46万 - 项目类别:
Mitochondrial Haplotype Influences LV Dysfunction in Heart Failure
线粒体单倍型影响心力衰竭中的左心室功能障碍
- 批准号:
8301933 - 财政年份:2012
- 资助金额:
$ 29.46万 - 项目类别:
Development of mitochondrially targeted antioxidants for diabetic therapy
开发用于糖尿病治疗的线粒体靶向抗氧化剂
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7268213 - 财政年份:2007
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