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).

石棉通过未完全阐明的机制引起石棉和恶性肿瘤。程度肺泡上皮细胞（AEC）损伤和修复是毒性的纤维基因的关键决定因素石棉等代理。以前的研究，包括来自我们小组的研究，已经确定了一些有助于石棉的不利影响以及保护性的策略的重要因素。我们已经表明了线粒体电子传输链的铁衍生的活性氧（ROS）介导石棉诱导的AEC DNA损伤和p53-和线粒体调节（内在）的凋亡死亡道路。我们最近的数据暗示了一种新型机制的重要作用线粒体人类8-氧气氨酸-DNA糖基酶1（MT-HOGG1）可防止氧化剂诱导的固有AEC 通过保存线粒体刺激酶（ACO2）来凋亡。 BCL-2家庭成员对于监管至关重要凋亡尚不清楚特定的Bcl-2蛋白如何调节石棉诱导的AEC凋亡以及是否是否是否这对于介导石棉病至关重要。我们的假设是线粒体hogg1维护线粒体刺激酶对衰减石棉诱导的AEC线粒体（MT）DNA损伤是由线粒体ROS造成的导致Bax/Bak内在的AEC凋亡和肺纤维化的产生。我们未来5年将检查的具体目标包括：（1）确定MT-HOGG1的ACO2保存是否对减弱石棉很重要（Crocicolite和Libby闪石）诱导的AEC mtDNA损伤，导致内在凋亡。我们还将利用OGG1 - / - 和OGG1过表达小鼠来评估OGG1之间的关系维护AEC ACO2水平，凋亡和石棉病。（2）评估小分子（例如EUK-134或OGG1裂解分子）是否保护ACO2。我们将还利用石棉的鼠模型来确定EUK-134是否会减弱AEC线粒体ROS 产生，ACO2和凋亡的减少以及肺纤维化。（3）确定无法保护AEC线粒体ROS的TFAMFL/FL小鼠是否受到保护反对石棉诱导的AEC凋亡和纤维化。我们还将评估小鼠是否与在肺泡上皮处有条件损失的BAX/BAK受到保护，以防止石棉病。这些研究应洞悉石棉诱导的AEC mtDNA的机制损伤和线粒体调节的细胞凋亡，可能导致肺纤维化。重要的是，石棉范式可能会提供有关其他肺部疾病的病理生理事件的新信息确定可能被证明可用于预防肺纤维化和/或肺的新型管理方法暴露于各种肺毒素（例如石棉，香烟烟，颗粒物等）之后的癌症。