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: 10990669
• 负责人: Karina Serban
• 金额: $ 73.66万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10990669
• 关键词: Decay; accelerating; factor; CD55; protects

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 inflammation and 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 which members of the lectin complement pathway are necessary to induce complement deposition in the lung, type-2 alveolar epithelial (AT2) cell dysfunction, and emphysema during CS exposure. In Aim 2 we will investigate whether decay accelerating factor (CD55), a complement regulator is required to protect against lectin complement deposition on AT2, preventing AT2 cell injury, death, and impaired proliferation. In Aim 3 we propose a translational approach to develop a composite plasma complement activity score encompassing complement proteins and their regulators that could identify smokers at risk and early emphysema individuals. My proposal addresses the clinically relevant question whether harnessing membrane CD55 expression and signaling in AT2 cells can prevent lectin complement deposition and activation, ameliorating AT2 dysfunction and emphysema development in relevant murine models of CS exposure. Our animal 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 platform, SomaScan. Validated SomaScan measurements using standard complement activity tests, total complement hemolytic activity (CH50) and Wieslab lectin pathway activity are used to develop a “complement activity score”. We will test the ability of complement activity score to predict clinical and radiological parameters of distal lung injury 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诱导的炎症和肺气肿样的空域增强，而无差异抑制 补充对病原体的反应。在AIM 1中，我们建议研究CS诱导的新机制 肺部损伤，重点关注讲座完成途径的哪些成员 肺中的补体沉积，2型肺泡上皮（AT2）细胞功能障碍和CS期间的肺气肿 接触。在AIM 2中，我们将调查衰减加速因子（CD55），补体调节剂是否是 防止AT2上预防讲座完成存款所需，防止AT2细胞受伤，死亡和 增殖受损。在AIM 3中，我们提出了一种转化方法来开发复合等离子体 补充活动评分包括补充蛋白质及其调节剂，可以识别吸烟者 有风险和早期肺气肿的人。我的提议解决了临床上相关的问题是否 利用AT2细胞中的膜CD55表达和信号传导可以防止讲座完成沉积 在相关的CS相关鼠模型中，激活，改善AT2功能障碍和肺气肿的发育 接触。我们的动物研究是通过对补体蛋白质和调节剂的测量来完成的 使用A的有或没有COPD的活性吸烟者的血浆水平和活性使用A 多路复用平台，索马斯加。使用标准完成活动测试进行了验证的SOMASCAN测量， 总完成溶血活性（CH50）和Wieslab讲座途径活动用于发展 “补充活动得分”。我们将测试补体活动评分预测临床和 盘状肺损伤进展的放射学参数。 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。