Mitochondrial regulation of macrophage activation in Chronic Obstructive Pulmonary Disease

慢性阻塞性肺疾病中巨噬细胞活化的线粒体调节

• 批准号: 10742904
• 负责人: Justin Sui
• 金额: $ 4.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10742904
• 关键词: Acids; Address; Adenine Nucleotide Translocase; Air; Alveolar; Alveolar Macrophages; American; Architecture; Biology; Bone Marrow; Bronchoalveolar Lavage; Carrier Proteins; Cause of Death; Cell Line; Cells; Cellular Metabolic Process; Cellular biology; Chronic; Chronic Obstructive Pulmonary Disease; Clinical; Data; Data Set; Development; Disease; Disease Progression; Epithelium; Equilibrium; Exposure to; Functional disorder; Generations; Genetic Transcription; Genus Hippocampus; Glutathione; Glutathione Reductase; Immune; Inflammation; Inflammatory; Inflammatory Response; Interleukin-4; Knock-out; Knockout Mice; Link; Liquid substance; Lung; Lung diseases; Macrophage; Macrophage Activation; Measures; Mediating; Membrane; Mentors; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mus; NADP; Oxidation-Reduction; Pathogenesis; Pathway interactions; Phagocytosis; Phenotype; Physicians; Play; Production; Pulmonary Emphysema; Pulmonary alveolar structure; Reactive Oxygen Species; Regulation; Research Personnel; Research Training; Respiration; Risk Factors; Role; SLC25A4 gene; Scientist; Small Interfering RNA; Smoke; Structure of parenchyma of lung; Testing; Time; Tissues; Training; United States; Western Blotting; Wild Type Mouse; airway inflammation; airway remodeling; cigarette smoke; cytokine; efficacious treatment; experience; experimental study; exposure to cigarette smoke; immune activation; inhibitor; knock-down; mitochondrial metabolism; mortality; novel therapeutic intervention; prevent; protein expression; reconstitution; respiratory; response; single-cell RNA sequencing; skills

Project Summary/Abstract Chronic obstructive pulmonary disease (COPD) is the fourth-leading cause of death in the United States. This lung disease is primarily associated with cigarette smoke usage and is characterized by damage to lung epithelium leading to macrophage-driven chronic inflammation, destruction of lung alveoli and airway thickening. This disease currently has no efficacious treatments and the initiating aberrant cellular pathways that lead to chronic inflammation in COPD remain unclear. Macrophage metabolism and activation are intimately linked, and dramatic shifts in metabolism have been observed depending on macrophage phenotype. Moreover, cigarette smoke is known to change cellular metabolism. The mitochondrial protein, adenine nucleotide translocase 1 (Ant1), is a critical regulator of cellular metabolism and ATP transport and the expression of this protein is downregulated in COPD lungs. To study the relationship between immune cellular metabolism and COPD pathogenesis, I utilize macrophages from Ant1-null mice in a smoke exposure model. I hypothesize that loss of Ant1 in alveolar macrophages impedes the activation of macrophages in the lung, thus preventing chronic inflammation that contributes to tissue remodeling and destruction in COPD. My proposal addresses the following aims: Aim 1: To determine the role of Ant1 in macrophage plasticity and inflammatory responses due to cigarette smoke. Aim 2: To determine the metabolic mechanisms by which Ant1 modulates macrophage activation in COPD pathogenesis. Together, these experiments uncover the function of immunometabolism in basic macrophage biology and in COPD pathogenesis. My proposal includes rigorous mentored research training with experienced mentors, the support of various collaborators, longitudinal clinical experience, and professional development pursuits. The scientific, technical, and professional skills gained during this training period will be critical in my development as an aspiring independent physician scientist researcher at the forefront of pulmonary immune cell biology.

项目摘要/摘要 慢性阻塞性肺疾病(COPD)是美国第四大死因。这 肺部疾病主要与吸烟有关，其特征是对肺的损害。 上皮细胞导致巨噬细胞驱动的慢性炎症，破坏肺泡和呼吸道 变厚了。该病目前尚无有效的治疗方法，其启动的异常细胞通路 导致COPD慢性炎症的原因尚不清楚。巨噬细胞的代谢和激活是 观察到依赖巨噬细胞的密切联系和代谢的戏剧性变化。 表型。此外，众所周知，香烟烟雾会改变细胞新陈代谢。线粒体蛋白， 腺嘌呤核苷酸转位酶1(ANT1)是细胞代谢和ATP转运的重要调节因子。 该蛋白在COPD肺中的表达下调。研究免疫细胞与机体免疫功能的关系 代谢和COPD发病机制，我利用ANT1缺失小鼠的巨噬细胞在烟雾暴露模型中。我 假设肺泡巨噬细胞中ANT1的缺失阻碍了肺内巨噬细胞的激活，因此 预防慢性阻塞性肺疾病中导致组织重塑和破坏的慢性炎症。我的建议 解决以下目标：目标1：确定ANT1在巨噬细胞可塑性和炎症中的作用 因吸烟而产生的反应。目的2：确定ANT1调节的代谢机制 巨噬细胞活化在慢性阻塞性肺疾病发病机制中的作用总而言之，这些实验揭示了 基础巨噬细胞生物学和COPD发病机制中的免疫代谢。我的建议包括严格的 由经验丰富的导师指导的研究培训，各种合作者的支持，纵向临床 经验丰富，追求专业发展。获得的科学、技术和专业技能 在这段培训期间，对于我作为一名有抱负的独立内科科学家的发展至关重要 处于肺免疫细胞生物学前沿的研究人员。