Decay accelerating factor (CD55) protects against lectin pathway-mediated AT2 cell dysfunction in cigarette smoke-induced emphysema

衰变加速因子 (CD55) 可防止香烟烟雾引起的肺气肿中凝集素途径介导的 AT2 细胞功能障碍

• 批准号: 10737359
• 负责人: Karina Serban
• 金额: $ 76.04万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2023-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10737359
• 关键词: Address; Alveolar; Alveolar Cell; Alveolus; Automobile Driving; Binding; Biological Markers; Blood capillaries; Bone Marrow; Brain; CD55 Antigens; Cell Death; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell membrane; Cells; Chimera organism; Chronic Obstructive Pulmonary Disease; Cigarette smoke-induced emphysema; Clinical; Clinical Trials; Complement; Complement Activation; Complement Membrane Attack Complex; Complex; Data; Deposition; Development; Disease; Distal; Dropout; Enrollment; Ensure; Epithelial Cell Proliferation; Epithelial Cells; Foundations; Functional disorder; Hematopoietic; Homeostasis; Host Defense; Human; Impairment; Individual; Inflammation; Injury; Lectin; Lung; MASP2 gene; Mannose Binding Lectin; Measurement; Measures; Mediating; Membrane; Mus; Organ; Organoids; Orphan; Pathogenesis; Pathway interactions; Patients; Phenotype; Plasma; Pre-Eclampsia; Proliferating; Proteins; Proteomics; Pulmonary Emphysema; Receptor Activation; Receptor Protein-Tyrosine Kinases; Regression Analysis; Risk; Role; Serine Protease; Signal Transduction; Smoker; Specimen; Sterility; Technology; Testing; Tissues; Vasculitis; alveolar epithelium; antimicrobial; cell injury; cigarette smoke; cigarette smoke-induced; cigarette smoke-induced lung injury; cigarette smoking; clinically relevant; cohort; complement pathway; epithelial injury; exposure to cigarette smoke; immune activation; improved; in vivo; injured; kidney cell; loss of function; lung injury; member; mouse model; next generation; novel; pathogen; pharmacologic; preservation; prevent; proliferation potential; receptor; response; risk stratification; therapeutic target; translational approach

Project summary The mechanisms by which cigarette smoke (CS) activates the complement cascade to cause distal lung sterile injury and progression to COPD are not completely understood. Considering the critical role of complement in pathogen-induced inflammation, selective inhibition of the lectin complement pathway may result in decreased CS-induced emphysema-like airspace enlargement without an indiscriminate inhibition of complement’s response to pathogens. In Aim 1 we propose to investigate a novel mechanism of CS-induced lung injury, focusing on members of the lectin complement pathway that are necessary to induce complement deposition in the lung, decreased type-2 alveolar epithelial (AT2) cell proliferation and differentiation into AT1 cells, resulting in emphysema. In Aim 2 we will investigate whether decay accelerating factor (CD55), a complement regulator is necessary and required to protect against lectin complement deposition on AT2, preventing cell injury and improving AT2 proliferation / differentiation. In Aim 3 we propose a translational approach to develop a plasma complement activity score encompassing complement proteins and their regulators that could identify emphysema progression in smokers at risk and early COPD individuals. My proposal addresses the clinically relevant question whether harnessing membrane CD55 expression and signaling in AT2 cells can prevent lectin complement deposition and improve AT2 proliferation and differentiation mitigating emphysema development. Our ex-vivo and in-vivo murine studies are accompanied by measurements of complement proteins and regulators levels and activity in plasma from active smokers with and without COPD enrolled in COPDGene using a multiplex proteomic platform, SomaScan. Multiple complement SomaScan proteins are used to develop a “complement activity score” to help predict emphysema progression. Completion of this project will provide compelling experimental evidences that targeting lectin pathway activation and preserving membrane CD55 expression on AT2 cells ameliorates distal lung injury in murine models of emphysema and it can be harnessed as next generation biomarkers in human COPD disease. Our newly complement activity score could identify smokers at risk and early COPD subjects in future research and pharmacological clinical trials. The complementary expertise of our team, the translational aspect of the proposal, and access to well-phenotyped human specimens increase the relevance and chance of successful completion of this project.

项目概要 香烟烟雾（CS）激活补体级联导致远端肺不育的机制 考虑到补体在慢性阻塞性肺病（COPD）中的关键作用，尚不完全清楚。 病原体引起的炎症，选择性抑制凝集素补体途径可能会导致 CS 诱导的肺气肿样空腔扩大，但不无差别地抑制补体 在目标 1 中，我们建议研究 CS 引起的肺损伤的新机制， 重点关注诱导补体沉积所必需的凝集素补体途径的成员 在肺部，2 型肺泡上皮 (AT2) 细胞增殖和分化为 AT1 细胞减少， 导致肺气肿 在目标 2 中，我们将研究腐烂加速因子 (CD55) 是否是一种补体。 调节剂对于防止凝集素补体沉积在 AT2 上是必要且必需的，从而防止细胞 在目标 3 中，我们提出了一种转化方法来开发。 血浆补体活性评分，包括补体蛋白及其调节因子，可以识别 我的建议涉及临床上吸烟者和早期慢性阻塞性肺病患者的肺气肿进展。 相关问题：利用 AT2 细胞膜 CD55 表达和信号传导是否可以预防 凝集素补体沉积并改善 AT2 增殖和分化，减轻肺气肿 我们的体外和体内小鼠研究伴随着补体的测量。 患有和不患有慢性阻塞性肺病的活跃吸烟者血浆中蛋白质和调节剂的水平和活性 COPDGene 使用多重蛋白质组学平台，SomaScan 多重补体 SomaScan 是蛋白质。 用于制定“补体活动评分”以帮助预测肺气肿进展。 该项目的完成将为靶向凝集素途径提供令人信服的实验证据 AT2 细胞上的激活和膜保护 CD55 表达可改善小鼠远端肺损伤 肺气肿模型，它可以用作人类慢性阻塞性肺病的下一代生物标志物。 新的补充活动评分可以在未来的研究中识别处于危险中的吸烟者和早期慢性阻塞性肺病受试者 我们团队的互补专业知识，转化方面。 提案以及获得表型良好的人类标本增加了相关性和成功的机会 该项目的完成。