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：
8295860
负责人：
DAVID W KAMP
金额：
$ 32.96万
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/8295860
关键词：
8-Oxoguanine DNA Glycosylase AGTR2 gene Aconitate Hydratase Adverse effects Air Alveolar Amphiboles Animal Model Antioxidants Apoptosis Asbestos Asbestosis Attenuated 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 Proteins 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

DESCRIPTION (provided by applicant): 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). PUBLIC HEALTH RELEVANCE: Asbestos-related lung diseases (asbestosis, bronchogenic lung cancer and mesothelioma) continue to pose serious health concerns worldwide, yet the pathogenesis is incompletely understood. The proposed studies should provide insight into the molecular mechanisms underlying asbestos-induced alveolar epithelial cell (AEC) cell death (apoptosis), which is an important initial event leading to fibrosis and carcinogenesis following asbestos exposure as well as in other more common diseases, such as idiopathic pulmonary fibrosis and lung cancer for which more effective management strategies are clearly needed. Specifically, we investigate the role of mitochondrial DNA repair enzyme (hOgg1) and aconitase in preventing asbestos (crocidolite and Libby amphibole)-induced AEC apoptosis as well as the role of AEC mitochondria-derived ROS and down-stream Bax activation.

描述（由申请人提供）：石棉通过未完全阐明的机制引起的石棉和恶性肿瘤。肺泡上皮细胞（AEC）损伤和修复的程度是毒性剂（例如石棉）纤维化潜力的关键决定因素。先前的研究，包括来自我们小组的研究，已经确定了导致石棉不利影响以及保护性策略的一些重要因素。我们已经表明，来自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）死亡途径的AEC DNA损伤和凋亡。我们最新的数据暗示了一种新型机制的重要作用，通过这种机制，线粒体人8-氧气氨基-DNA糖基酶1（MT-HOGGG1）可通过保持线粒体腺苷酶（ACO2）来防止氧化剂诱导的内在AEC凋亡。 BCL-2家族成员对于调节凋亡至关重要，但尚不清楚特定的Bcl-2蛋白如何调节石棉诱导的AEC凋亡以及这对于介导石棉病至关重要。我们的假设是，线粒体的线粒体HOGG1保留线粒体刺刺酶对于减弱石棉诱导的AEC线粒体（MT）DNA损伤至关重要，这导致线粒体ROS产生导致Bax/Bak Intinsic AEC凋亡和肺纤维化。我们将在未来5年中进行检查的具体目的包括：（1）确定MT-HOGG1的ACO2保存是否在减轻石棉（Crocidolite和Libby Amphibole）诱导的AEC mTDNA损害方面是否重要，从而导致内在凋亡。我们还将利用OGG1 - / - 和OGG1过表达小鼠来评估OGG1 AEC ACO2水平，凋亡和石棉病之间的关系。（2）评估小分子（例如EUK-134或OGG1裂解分子）是否保护ACO2。我们还将利用一种石棉的鼠模型来确定EUK-134是否会减少AEC线粒体ROS的产生，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产生的TFAMFL/FL小鼠是否受到石棉诱导的AEC凋亡和纤维化的保护。我们还将评估在肺泡上皮处有条件损失的小鼠免受石棉病的保护。这些研究应提供有关石棉诱导的AEC MTDNA损伤和线粒体调节的细胞凋亡的洞察力，从而导致肺纤维化。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，这些信息将识别出可能被证明可用于预防肺纤维化和/或肺癌有用的新型管理方法（例如，在各种肺毒素中暴露（例如石棉，烟雾，颗粒，颗粒物）等）。公共卫生相关性：与石棉相关的肺部疾病（石棉，支气管肺癌和间皮瘤）在全球范围内继续引起严重的健康问题，但尚不完全了解这种发病机理。拟议的研究应提供对石棉诱导的肺泡上皮细胞（AEC）细胞死亡（凋亡）的分子机制的深入了解，这是一个重要的初始事件，导致棉花暴露后纤维化和癌变后，以及其他更常见的疾病以及其他常见的肺纤维纤维纤维纤维癌和肺癌的策略，并有效地有效地管理了其他常见的疾病。具体而言，我们研究了线粒体DNA修复酶（HOGG1）和丙OCONITAPE在预防石棉（鳄鱼丝和利比二氧苯甲酸）诱导的AEC凋亡以及AEC线粒体衍生的ROS和下游Bax Bax活化的作用。