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

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

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DAVID W KAMP其他文献

DAVID W KAMP的其他文献

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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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