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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：
DAVID W KAMP
金额：
$ 32.19万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
https://reporter.nih.gov/project-details/8429439
关键词：
8-Oxoguanine DNA Glycosylase AGTR2 gene Aconitate Hydratase Adverse effects Air Alveolar Amphiboles Animal Model Antioxidants Apoptosis Asbestos Asbestosis Attenuated BCL-2 Protein BCL2 gene Biological Preservation Bronchogenic Carcinoma Cell Death Cessation of life Cleaved cell Crocidolite Asbestos DNA Damage DNA Repair Enzymes Data Disease Electron Transport Epithelial Cells Event Exposure to Family member Fibrosis Functional disorder Hamman-Rich syndrome Health Human In Vitro Iron Lung Lung diseases Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Mesothelioma Mitochondria Mitochondrial DNA Modeling Molecular Mus Outcome Oxidants Particulate Matter Pathogenesis Pathway interactions Patients Prevention Production Pulmonary Fibrosis Reactive Oxygen Species Regimen Resistance Role Stream Tobacco Toxic Environmental Substances Toxin alveolar epithelium carcinogenesis cell injury cigarette smoking in vivo injury and repair insight mitochondrial dysfunction novel overexpression prevent small 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