Mitigation of asbestos induced alveolar epithelial cell injury
减轻石棉引起的肺泡上皮细胞损伤
基本信息
- 批准号:8429439
- 负责人:
- 金额:$ 32.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-03-01 至 2016-12-31
- 项目状态:已结题
- 来源:
- 关键词:8-Oxoguanine DNA GlycosylaseAGTR2 geneAconitate HydrataseAdverse effectsAirAlveolarAmphibolesAnimal ModelAntioxidantsApoptosisAsbestosAsbestosisAttenuatedBCL-2 ProteinBCL2 geneBiological PreservationBronchogenic CarcinomaCell DeathCessation of lifeCleaved cellCrocidolite AsbestosDNA DamageDNA Repair EnzymesDataDiseaseElectron TransportEpithelial CellsEventExposure toFamily memberFibrosisFunctional disorderHamman-Rich syndromeHealthHumanIn VitroIronLungLung diseasesMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMediatingMesotheliomaMitochondriaMitochondrial DNAModelingMolecularMusOutcomeOxidantsParticulate MatterPathogenesisPathway interactionsPatientsPreventionProductionPulmonary FibrosisReactive Oxygen SpeciesRegimenResistanceRoleStreamTobaccoToxic Environmental SubstancesToxinalveolar epitheliumcarcinogenesiscell injurycigarette smokingin vivoinjury and repairinsightmitochondrial dysfunctionnoveloverexpressionpreventsmall molecule
项目摘要
Asbestos causes asbestosis and malignancies by mechanisms that are not fully elucidated. The extent
of alveolar epithelial cell (AEC) injury and repair are critical determinants of the fibrogenic potential of toxic
agents such as asbestos. Previous studies, including ones from our group, have identified some of the
important factors contributing to the adverse effects of asbestos as well as strategies that are protective. We
have shown that iron-derived reactive oxygen species (ROS) from the mitochondria electron transport chain
mediate asbestos-induced AEC DNA damage and apoptosis by a p53- and mitochondria-regulated (intrinsic)
death pathway. Our more recent data implicate an important role for a novel mechanism by which
mitochondrial human 8-oxoguanine-DNA glycosylase 1 (mt-hOgg1) prevents oxidant-induced intrinsic AEC
apoptosis by preserving mitochondrial aconitase (Aco2). Bcl-2 family members are crucial for regulating
apoptosis yet it is unclear how specific Bcl-2 proteins modulate asbestos-induced AEC apoptosis and whether
this is essential for mediating asbestosis.
Our HYPOTHESIS is that mitochondrial hOgg1 preservation of mitochondrial aconitase is important for
attenuating asbestos-induced AEC mitochondrial (mt)DNA damage resulting from mitochondrial ROS
production that leads to Bax/Bak intrinsic AEC apoptosis and pulmonary fibrosis.
Our SPECIFIC AIMS that will be examined over the next 5 years include:
(1) To determine whether mt-hOgg1 preservation of Aco2 is important in attenuating asbestos
(crocidolite and Libby amphibole)-induced AEC mtDNA damage that results in intrinsic apoptosis. We
will also utilize Ogg1-/- and Ogg1 overexpressing mice to genetically assess the relationship between Ogg1
preservation of AEC Aco2 levels, apoptosis and asbestosis.
(2) To assess whether a small molecule (e.g. Euk-134 or Ogg1 cleaved molecule) protects Aco2. We will
also utilize a murine model of asbestosis to determine whether Euk-134 attenuates AEC mitochondrial ROS
production, reductions in Aco2 and apoptosis as well as pulmonary fibrosis.
(3) To determine whether TFAMfl/fl mice, incapable of AEC mitochondrial ROS production, are protected
against asbestos-induced AEC apoptosis and fibrosis. We will also assess whether mice with
conditional loss of Bax/Bak at the alveolar epithelium are protected against asbestosis.
These studies should provide insight into the mechanisms underlying asbestos-induced AEC mtDNA
damage and mitochondria-regulated apoptosis that can cause pulmonary fibrosis. Importantly, the asbestos
paradigm may provide new information about the pathophysiologic events of other lung diseases that will
identify novel management approaches that may prove useful in preventing pulmonary fibrosis and/or lung
cancer following exposure to various pulmonary toxins (e.g. asbestos, cigarette smoke, particulate matter etc).
石棉引起石棉肺和恶性肿瘤的机制尚未完全阐明。广度
肺泡上皮细胞(AEC)损伤和修复是毒物致纤维化潜能的关键决定因素
石棉等试剂。之前的研究,包括我们小组的研究,已经确定了一些
造成石棉不利影响的重要因素以及具有防护性的战略。我们
已经表明,来自线粒体电子传输链的铁源性活性氧物种(ROS)
P53和线粒体调节(内在)介导石棉诱导的AEC DNA损伤和细胞凋亡
死亡之路。我们最近的数据暗示了一种新的机制的重要作用,通过这种机制
线粒体人8-氧鸟嘌呤-DNA糖基酶1(mt-hOgg1)对氧化诱导的内源性血管内皮细胞的保护作用
保存线粒体乌头酸酶(ACO2)诱导的细胞凋亡。BCL-2家族成员在调控中起关键作用
目前尚不清楚特定的Bcl-2蛋白如何调节石棉诱导的AEC凋亡,以及
这对于调节石棉肺是必不可少的。
我们的假设是,线粒体hOgg1对线粒体乌头酸酶的保存对
减轻石棉诱导的线粒体ROS引起的AEC线粒体DNA损伤
导致Bax/Bak固有的AEC凋亡和肺纤维化的产生。
我们将在未来5年审查的具体目标包括:
(1)确定mt-hOgg1保存ACO2是否对减少石棉很重要
(青石棉和Libby闪石)诱导AEC线粒体DNA损伤,导致内在细胞凋亡。我们
还将利用Ogg1-/-和Ogg1过度表达的小鼠来从基因上评估Ogg1和Ogg1之间的关系
AEC ACO2水平的保存、细胞凋亡和石棉肺。
(2)评估小分子(例如EUK-134或Ogg1裂解分子)是否保护ACO2。我们会
也利用石棉肺的小鼠模型来确定EUK-134是否减弱AEC线粒体ROS
产生、ACO2减少、细胞凋亡以及肺纤维化。
(3)确定不能产生AEC线粒体ROS的TFAMf1/fl小鼠是否受到保护
抗石棉诱导的血管内皮细胞凋亡和纤维化。我们还将评估老鼠是否患有
肺泡上皮细胞Bax/Bak的条件性丢失对石棉肺有保护作用。
这些研究应该有助于深入了解石棉诱导的AEC mtDNA的机制。
损伤和线粒体调节的细胞凋亡可导致肺纤维化。重要的是,石棉
范式可能提供关于其他肺部疾病的病理生理事件的新信息,这些事件将
确定在预防肺纤维化和/或肺方面可能有用的新管理方法
暴露于各种肺部毒素(如石棉、香烟烟雾、颗粒物等)后导致的癌症。
项目成果
期刊论文数量(0)
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{{ truncateString('DAVID W KAMP', 18)}}的其他基金
Mitigation of asbestos induced alveolar epithelial cell injury
减轻石棉引起的肺泡上皮细胞损伤
- 批准号:
8295860 - 财政年份:2012
- 资助金额:
$ 32.19万 - 项目类别:
Mitigation of asbestos induced alveolar epithelial cell injury
减轻石棉引起的肺泡上皮细胞损伤
- 批准号:
8593294 - 财政年份:2012
- 资助金额:
$ 32.19万 - 项目类别:
Mitigation of asbestos induced alveolar epithelial cell injury
减轻石棉引起的肺泡上皮细胞损伤
- 批准号:
8787738 - 财政年份:2012
- 资助金额:
$ 32.19万 - 项目类别:
Mechanisms of Asbestos-Induced Alveolar Epithelial Cell Injury
石棉引起的肺泡上皮细胞损伤的机制
- 批准号:
8445153 - 财政年份:2011
- 资助金额:
$ 32.19万 - 项目类别:
Mechanisms of Asbestos-Induced Alveolar Epithelial Cell Injury
石棉引起的肺泡上皮细胞损伤的机制
- 批准号:
8696778 - 财政年份:2011
- 资助金额:
$ 32.19万 - 项目类别:
Mechanisms of Asbestos-Induced Alveolar Epithelial Cell Injury
石棉引起的肺泡上皮细胞损伤的机制
- 批准号:
10392322 - 财政年份:2011
- 资助金额:
$ 32.19万 - 项目类别:
Mechanisms of Asbestos-Induced Alveolar Epithelial Cell Injury
石棉引起的肺泡上皮细胞损伤的机制
- 批准号:
8141684 - 财政年份:2011
- 资助金额:
$ 32.19万 - 项目类别:
Mechanisms of Asbestos-Induced Alveolar Epithelial Cell Injury
石棉引起的肺泡上皮细胞损伤的机制
- 批准号:
9136340 - 财政年份:2011
- 资助金额:
$ 32.19万 - 项目类别:
Mechanisms of Asbestos-Induced Alveolar Epithelial Cell Injury
石棉引起的肺泡上皮细胞损伤的机制
- 批准号:
8397570 - 财政年份:2011
- 资助金额:
$ 32.19万 - 项目类别:
Mechanisms of Asbestos-Induced Alveolar Epithelial Cell Injury
石棉引起的肺泡上皮细胞损伤的机制
- 批准号:
9273259 - 财政年份:2011
- 资助金额:
$ 32.19万 - 项目类别:














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