Cell survival and death in oxidant lung injury

氧化性肺损伤中的细胞存活和死亡

基本信息

批准号：
8468006
负责人：
Michael A O'Reilly
金额：
$ 36.77万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8468006
关键词：
A549 Adolescent Adult Age Air Alveolar Apoptotic Back Birth Blood Pressure Bronchopulmonary Dysplasia Cartoons Cell Cycle Cell Cycle Arrest Cell Death Cell Differentiation process Cell Line Cell Nucleus Cell Survival Cells Child Mortality Chronic Cleaved cell DNA DNA Damage Disease Attributes Environmental air flow Enzymes Epithelial Epithelial Cell Proliferation Epithelial Cells Epithelium Exposure to Functional disorder Gene Expression Gene Expression Profiling Genes Genetic Goals Growth Hyperoxia Lead Longevity Lung Lung diseases Mitochondria Mitochondrial DNA Mitochondrial Diseases Modeling Mus Muscle Neonatal Neurons Newborn Infant Nuclear Oxidants Oxygen Oxygen measurement, partial pressure, arterial Phosphorylation Predisposition Protein p53 Pulmonary Hypertension Respiration Respiratory physiology Retroviridae Risk Factors Serine Signal Pathway Signal Transduction Structure of respiratory epithelium Testing Therapeutic Uses Time Tissues Transgenic Mice Tumor Suppressor Proteins Virus Diseases age related aged base cell growth inhibitor/antagonist lung development lung injury mitochondrial dysfunction mitochondrial genome neonate novel novel therapeutics oxidative damage oxygen toxicity postnatal premature respiratory response restriction enzyme surfactant

项目摘要

DESCRIPTION (provided by applicant): Premature exposure to oxygen is a major risk factor for bronchopulmonary dysplasia (BPD), a chronic form of lung disease frequently seen in neonates that is characterized as an arrest in lung development. Although the therapeutic use of exogenous surfactant and milder ventilation strategies has reduced mortality, children and adolescents born prematurely have reduced lung function, increased susceptibility to respiratory viral infections, and age-associated increases in blood pressure. Hence there is an urgent need to understand how oxygen permanently disrupts growth of the developing lung. Recent studies suggest damage to mitochondria is a component of oxygen-induced newborn lung disease because elevated levels of oxygen (hyperoxia) suppress mitochondrial respiration and damage mitochondrial DNA. To determine whether cells activate retrograde signaling back to the nucleus to control gene expression in response to mitochondrial DNA damage, epithelial cells were infected with retroviruses expressing enzymes that cause strand breaks in mitochondrial or nuclear DNA. Like hyperoxia, damage to mitochondrial or nuclear DNA stimulated expression of the tumor suppressor protein p53. In contrast, mitochondrial targeting of an enzyme that only cuts nuclear DNA failed to activate p53, but did so when targeted to the nucleus. When activated by mitochondrial DNA damage, p53 stimulated expression of nuclear genes that inhibited cell growth and enhanced cell survival. These findings suggest the cell reacts to mitochondrial DNA damage with a classic nuclear DNA damage response, and that this response inhibits cell growth, perhaps in anticipation of impending mitochondrial dysfunction and energy depletion. Based upon these findings, we now propose to test the hypothesis that mitochondrial DNA damage is a component of how hyperoxia activates p53 signaling and disrupts postnatal lung development. We will test this hypothesis using novel retroviruses and transgenic mice capable of conditionally damaging mitochondrial DNA in respiratory epithelial cells. Understanding how cells respond specifically to oxygen-induced mitochondrial DNA damage is highly significant because it could lead to new therapeutic opportunities for reducing oxygen-toxicity to the developing lung as well as age-related diseases attributed to oxygen toxicity.

描述（由申请人提供）：过早接触氧气是支气管肺发育不良（BPD）的主要危险因素，这是一种在新生儿中经常看到的慢性肺部疾病形式，其特征在于肺部发育中被捕。尽管外源表面活性剂和温和通气策略的治疗使用降低了死亡率，但出生的儿童和青少年过早地降低了肺功能，增加了对呼吸道病毒感染的易感性，以及与年龄相关的血压升高。因此，迫切需要了解氧气如何永久破坏发育中的肺的生长。最近的研究表明，对线粒体的损害是氧诱导的新生儿疾病的组成部分，因为氧气升高（高氧）抑制了线粒体呼吸和损伤线粒体DNA。为了确定细胞是否将逆行信号传递回到细胞核中，以控制对线粒体DNA损伤的基因表达，上皮细胞用表达酶的逆转录病毒感染，这些酶在线粒体或核DNA中引起链断裂的酶。像高氧一样，对线粒体或核DNA的损害刺激了肿瘤抑制蛋白p53的表达。相比之下，仅切入核DNA的酶的线粒体靶向无法激活p53，但在靶向核时这样做。当通过线粒体DNA损伤激活时，p53刺激了抑制细胞生长并增强细胞存活的核基因的表达。这些发现表明，细胞对线粒体DNA损伤有反应，并具有经典的核DNA损伤反应，并且这种反应抑制了细胞的生长，也许是因为即将发生的线粒体功能障碍和能量耗竭。基于这些发现，我们现在建议测试线粒体DNA损伤是高氧激活p53信号传导并破坏产后肺发育的组成部分的假设。我们将使用新型逆转录病毒和能够在呼吸性上皮细胞中有条件损害线粒体DNA的转基因小鼠进行检验。了解细胞如何对氧诱导的线粒体DNA损伤有特殊反应是非常重要的，因为它可能导致新的治疗机会，以降低发育中的肺部以及归因于氧气毒性的年龄相关疾病。