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.

项目摘要 香烟烟（CS）激活完成级联以引起远端肺无菌的机制 尚未完全了解伤害和进展为COPD。考虑完成的关键作用 病原体引起的炎症，对讲座完成途径的选择性抑制可能导致下降 CS诱导的肺气肿状空域增强，而无需不加区分的抑制作用 对病原体的反应。在AIM 1中，我们建议研究CS诱导的肺损伤的新机制， 专注于诱导完成沉积所必需的讲座完成途径的成员 在肺中，改善2型肺泡上皮（AT2）细胞增殖，并分化为AT1细胞， 导致肺气肿。在AIM 2中，我们将调查衰减加速因子（CD55）是否完成 调节器是必需的，并且需要预防AT2上的练习素完成沉积，以防止细胞 在目标3中，我们提出了一种转化方法来发展 血浆补体活动评分包括补体蛋白质及其调节剂，可以识别 吸烟者和早期COPD患者的肺气肿进展。我的建议在临床上解决 相关问题是否利用AT2细胞中的膜CD55表达和信号传导是否可以防止 凝集素完成沉积并改善AT2增殖和分化减轻肺气肿 发展。我们的前体体和体内鼠研究是通过完成的测量来完成的 蛋白质和调节剂的水平和活跃吸烟者的血浆中的活性和活性 使用多重蛋白质组学平台SOMASCAN的COPDGENE。多个完成的somascan蛋白是 用于开发“补体活动评分”，以帮助预测肺气肿的进展。 该项目的完成将提供引人入胜的实验证据，以讲座途径 AT2细胞上的激活和保存膜CD55表达可以改善鼠的圆盘肺损伤 肺气肿的模型及其可以作为人类COPD疾病中的下一代生物标志物进行。我们的 新近补充的活动评分可以在未来的研究中识别有风险和早期COPD受试者的吸烟者，并且 药理临床试验。我们团队的完成专家，翻译的方面 提案，并获得良好的人类标本增加了成功的相关性和机会 完成此项目。