Mitochondrial DNA: a target and effector of pulmonary epithelial cell injury

线粒体DNA：肺上皮细胞损伤的靶点和效应器

• 批准号: 8893565
• 负责人: Bartosz Rafal Szczesny
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-16 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893565
• 关键词: Adult Respiratory Distress Syndrome; Affect; Allergens; Allergic; Ambrosia; Asthma; Attention; Bacterial DNA; Base Excision Repairs; Bioenergetics; Biology; Bronchoalveolar Lavage Fluid; Cell Death; Cell Death Signaling Process; Cell membrane; Cell physiology; Cells; Characteristics; Chronic Obstructive Airway Disease; Coupled; DNA; DNA Damage; DNA Repair; Data; Development; Disease; Epithelial Cells; Eukaryotic Cell; Event; Faculty; Free Radicals; Future; Generations; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Lesion; Link; Lung; Lung Lavage Fluid; Lung diseases; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mus; Mutagens; Necrosis; Nitrogen; Nuclear; Outcome; Oxidants; Oxidative Stress; Oxygen; Pathogenesis; Pathway interactions; Phase; Play; Pollen; Process; Pulmonary Inflammation; Research; Role; Science; Sentinel; Signal Pathway; Signal Transduction; Signaling Molecule; Single Strand Break Repair; Testing; Time; Tissues; allergic airway inflammation; base; cell injury; extracellular; extranuclear DNA; in vivo; inflammatory lung disease; innovation; lung injury; mitochondrial dysfunction; novel; novel therapeutic intervention; novel therapeutics; oxidative damage; public health relevance; receptor; repaired; response

 DESCRIPTION (provided by applicant): Pulmonary epithelial cells are key effectors as well as targets in the pathogenesis of various lung diseases. Oxidative stress in airways has been implicated as an early event in development of lung injury during asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and other lung diseases including lung cancer. Highly oxygenated tissues such as lungs are particularly prone to oxidative stress injury. Although mitochondrial DNA is highly susceptible to oxidant-induced damage, the pathogenic role of mitochondrial DNA damage has not been investigated in connection to the lung epithelial cell injury. Based on several lines of our in vitro and in vivo preliminary data, we put forward th novel hypothesis that damaged mitochondrial DNA acts as a novel sentinel molecule at the earliest phase of the induction of pro-inflammatory response in pulmonary epithelial cells. Mitochondrial DNA, as opposed to nuclear DNA, includes several characteristic features of bacterial DNA, making it particularly potent in inducing inflammatory response. By unraveling the active role of mitochondrial DNA damage in the promotion of pulmonary inflammation, this project is expected to identify new therapeutic directions to ameliorate its negative outcome. Our hypothesis will be comprehensively evaluated by combination of in vitro and in vivo studies by following aims: Aim 1. To elucidate the role of mitochondrial DNA-specific damage in the development of pro-inflammatory signaling in vitro; by analyzing changes of critical mitochondrial and cellular functions, and signaling pathways of the pro- inflammatory response including mechanism of oxidized mitochondrial DNA release and DNA-sensing receptors; all in response to mitochondrial DNA-specific damage. Aim 2. To elucidate the causative role of the mitochondrial DNA damage in the pulmonary inflammatory response in vivo by comprehensive analysis of the connection between oxidative damage to the mitochondrial DNA in the lungs, the presence of oxidized mitochondrial DNA in the alveolar lavage fluid, and inflammatory response in mouse airways. The previous view in the field of free radical biology and DNA injury was that damage to the DNA is a downstream consequence of oxidative and inflammatory lung injury. In contrast, our project will establish a new paradigm in the pathogenesis of pulmonary inflammatory diseases by demonstrating that mitochondrial DNA damage acts as an early causative step in induction of the inflammatory lung response. Understanding the molecular mechanisms of this process has the potential to formulate novel therapeutic approaches. Our unique expertise in DNA repair/damage, mitochondrial pathobiology and assembly of the collaborators makes us ideally suited to undertake this project. Moreover, R21 is ideal founding mechanism for junior faculty in order to develop successful R01 application in the near future.