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

基本信息

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
项目类别：
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

项目摘要

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）是美国的第四个领先原因。这肺部病主要与香烟烟的使用有关，其特征是肺部损害上皮导致巨噬细胞驱动的慢性炎症，肺肺泡和气道的破坏增厚。该疾病目前没有有效的治疗和引发异常的细胞途径导致COPD的慢性炎症尚不清楚。巨噬细胞代谢和激活是密切联系，并且已经观察到代谢的急剧转移，具体取决于巨噬细胞表型。此外，已知香烟会改变细胞代谢。线粒体蛋白，腺嘌呤核苷酸易位酶1（ANT1）是细胞代谢和ATP转运的关键调节剂以及该蛋白的表达在COPD肺中下调。研究免疫细胞之间的关系代谢和COPD发病机理，我在烟雾暴露模型中利用ANT1-NULL小鼠的巨噬细胞。我假设肺泡巨噬细胞中ANT1的丧失会阻碍肺中巨噬细胞的激活防止慢性炎症有助于COPD的组织重塑和破坏。我的建议解决以下目的：目标1：确定ANT1在巨噬细胞塑性和炎症中的作用由于烟雾而产生的反应。目标2：确定ANT1调节的代谢机制 COPD发病机理中的巨噬细胞激活。这些实验共同发现了基本巨噬细胞生物学和COPD发病机理中的免疫代谢。我的建议包括严格与经验丰富的导师的指导研究培训，各种合作者的支持，纵向临床经验和专业发展追求。获得的科学，技术和专业技能在这个培训期间，我作为有抱负的独立医师科学家的发展至关重要研究人员处于肺免疫细胞生物学的最前沿。