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).
石棉引起石棉沉滞和恶性肿瘤的机制尚未完全阐明。的程度
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 }}
DAVID W KAMP其他文献
DAVID W KAMP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('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: