Mitochondrial regulation of macrophage activation in Chronic Obstructive Pulmonary Disease

项目总结/摘要 慢性阻塞性肺疾病（COPD）是美国第四大死亡原因。这 肺部疾病主要与吸烟有关，其特征是肺损伤 上皮导致巨噬细胞驱动的慢性炎症，肺泡和气道的破坏 增厚这种疾病目前没有有效的治疗方法， 导致慢性阻塞性肺病慢性炎症的原因尚不清楚。巨噬细胞代谢和活化是 密切相关，并已观察到代谢的显着变化取决于巨噬细胞 表型。此外，香烟烟雾已知会改变细胞代谢。线粒体蛋白， 腺嘌呤核苷酸移位酶1（Ant1）是细胞代谢和ATP转运的关键调节剂， 这种蛋白质的表达在COPD肺中下调。研究免疫细胞与肿瘤细胞的关系， 代谢和COPD发病机制，我利用烟雾暴露模型中的Ant1-null小鼠的巨噬细胞。我 假设肺泡巨噬细胞中Ant1的缺失阻碍了肺中巨噬细胞的活化，因此 预防COPD中导致组织重塑和破坏的慢性炎症。我的提议 目的1：确定Ant1在巨噬细胞可塑性和炎症反应中的作用。 吸烟引起的反应。目的2：确定Ant1调节的代谢机制 巨噬细胞活化在COPD发病机制中的作用总之，这些实验揭示了 在基础巨噬细胞生物学和COPD发病机制中免疫代谢。我的建议包括严格的 有经验的导师指导的研究培训，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 在这个培训期间将是至关重要的，我的发展，作为一个有抱负的独立的医生科学家 肺免疫细胞生物学前沿的研究员。

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.