The Role of Adenine Nucleotide Translocase in Mitochondrial Dysfunction Associated Senescence in Chronic Obstructive Pulmonary Disease (COPD)

腺嘌呤核苷酸转位酶在慢性阻塞性肺病（COPD）线粒体功能相关衰老中的作用

• 批准号: 10633608
• 负责人: Corrine R Kliment
• 金额: $ 65.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633608
• 关键词: Abnormal Epithelial Cell; Adenine Nucleotide Translocase; Alveolar; Antioxidants; Area; Automobile Driving; Cause of Death; Cell Aging; Cell Cycle Arrest; Cell Line; Cell physiology; Cells; Cellular Metabolic Process; Chronic; Chronic Obstructive Pulmonary Disease; DNA Damage; Data; Disease Progression; Epithelial Cells; Equilibrium; Excision; Gene Expression; Genus Hippocampus; Goals; Homeostasis; Human; In Vitro; Inflammation; Injury; Knock-out; Knockout Mice; Knowledge; Lung; Lung diseases; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Mus; NADH; Obstructive Lung Diseases; Organoids; Outcome; Oxidation-Reduction; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Process; Production; Proliferating; Pulmonary Emphysema; Reactive Oxygen Species; Respiration; Role; Slice; Structure of parenchyma of lung; Testing; Therapeutic; Tissues; Transcriptional Regulation; United States; Work; airway obstruction; alveolar epithelium; bronchial epithelium; cigarette smoke; effective therapy; epithelial repair; exposure to cigarette smoke; gain of function; improved; in vivo; in vivo Model; inhibitor; insight; interest; knock-down; loss of function; lung repair; mitochondrial dysfunction; mitochondrial metabolism; mouse model; novel; novel therapeutic intervention; oncoprotein p21; prevent; progenitor; programs; repaired; response; restoration; senescence; stem cell function; stem cells; therapeutic development; therapeutic target

PROJECT SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the United States with no current therapies that significantly alter disease progression. Cigarette smoke (CS) is a major causative factor in COPD that results in mitochondrial dysfunction and reactive oxygen species (ROS). Alveolar epithelial type 2 cells (AEC2s) are essential progenitor cells for normal lung homeostasis (cell renewal) and epithelial repair after CS injury and in COPD. Mitochondrial dysfunction and cell senescence, a state of cell cycle arrest, have been implicated in COPD and may reduce AEC2 cell progenitor function and epithelial repair. The causative mechanisms and functional consequences of mitochondrial dysfunction on AEC2 senescence and epithelial repair in COPD remain major knowledge gaps and may provide new insights for the development of therapeutic approaches. The major goal of this proposal is to determine how mitochondrial dysfunction mediated by adenine nucleotide translocase 2 (ANT2) contributes to cellular senescence and abnormal epithelial cell repair in chronic obstructive pulmonary disease (COPD). Adenine nucleotide translocase 2 (ANT2) is a mitochondrial ATP transporter critical for cell metabolism and fate. We have shown that ANT2 gene expression is reduced in lung tissue from patients with COPD and that ANT2 knockdown in human bronchial epithelial cells results in reduced mitochondrial respiration (Kliment et al, J Cell Sci 2021). Our preliminary data show that human ANT2 is specifically reduced in AEC2s from COPD lungs. Knockdown of ANT2 in epithelial cells in vitro results in increased p21 and p16 (markers of senescence). In a mouse CS model of COPD, loss of ANT2 in alveolar epithelial cells results in enhanced lung destruction (emphysema), increased p21 and p16 in AEC2s, and increased ROS. This proposal will determine how ANT2 protects against emphysema by modulating ROS production, mitochondrial metabolism and senescence in AEC2 cells and epithelial repair after CS. Our study will determine the following: 1) To test the hypothesis that loss of ANT2 in AEC2 cells drives senescence by increasing ROS and the DNA damage response (DDR). 2) To test the hypothesis that loss of ANT2 shifts AEC2 metabolism and decreases repair capacity to promote COPD. 3) To test the hypothesis that therapeutic restoration of ANT2 or removal of senescent cells can protect against emphysema. The outcome of this proposal will define the mechanisms by which mitochondrial dysfunction and shifts towards glycolytic metabolism due to loss of ANT2 drives senescence and dysregulated epithelial repair in AEC2 cells in COPD. Elucidation of ANT2 as a major regulator of lung epithelial repair and senescence through mitochondrial dysfunction provides critical knowledge connecting these processes and will inform the discovery of new COPD therapies.

项目概要 慢性阻塞性肺疾病 (COPD) 是美国第四大死因 目前没有显着改变疾病进展的疗法。香烟烟雾（CS）是主要致病因素 慢性阻塞性肺病（COPD）会导致线粒体功能障碍和活性氧（ROS）。 2型肺泡上皮 细胞（AEC2）是正常肺稳态（细胞更新）和肺上皮修复的重要祖细胞。 CS 损伤和 COPD。线粒体功能障碍和细胞衰老（细胞周期停滞的一种状态）已被 与 COPD 有关，并可能降低 AEC2 细胞祖细胞功能和上皮修复。病因 线粒体功能障碍对 AEC2 衰老的机制和功能影响 COPD 中的上皮修复仍然是主要的知识空白，可能为研究提供新的见解 治疗方法的发展。该提案的主要目标是确定线粒体如何 腺嘌呤核苷酸转位酶 2 (ANT2) 介导的功能障碍导致细胞衰老 慢性阻塞性肺疾病（COPD）中的异常上皮细胞修复。腺嘌呤核苷酸转位酶 2 (ANT2) 是一种线粒体 ATP 转运蛋白，对细胞代谢和命运至关重要。我们已经证明 ANT2 COPD 患者肺组织中的基因表达减少，并且人类中 ANT2 敲低 支气管上皮细胞导致线粒体呼吸减少（Kliment 等人，J Cell Sci 2021）。我们的 初步数据表明，来自 COPD 肺部的 AEC2 中人类 ANT2 特异性降低。击倒 体外上皮细胞中的 ANT2 会导致 p21 和 p16（衰老标志物）增加。在小鼠 CS 模型中 在慢性阻塞性肺病 (COPD) 中，肺泡上皮细胞中 ANT2 的缺失会导致肺部破坏加剧（肺气肿）， AEC2 中的 p21 和 p16，并增加 ROS。该提案将确定 ANT2 如何防范 通过调节 AEC2 细胞中 ROS 产生、线粒体代谢和衰老来治疗肺气肿 CS后的上皮修复。我们的研究将确定以下内容： 1）检验以下假设： AEC2 细胞中的 ANT2 通过增加 ROS 和 DNA 损伤反应 (DDR) 来驱动衰老。 2）测试 假设 ANT2 的缺失会改变 AEC2 代谢并降低修复能力，从而促进 COPD。 3） 测试以下假设：治疗性恢复 ANT2 或去除衰老细胞可以预防 气肿。该提案的结果将定义线粒体功能障碍和 由于 ANT2 缺失导致衰老和上皮修复失调而转向糖酵解代谢 COPD 中的 AEC2 细胞。阐明 ANT2 作为肺上皮修复和衰老的主要调节因子 线粒体功能障碍提供了连接这些过程的关键知识，并将为这一发现提供信息 新的慢性阻塞性肺病疗法。