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 引起的炎症和肺气肿样空腔扩大，但没有不加选择地抑制 在目标 1 中，我们补充建议研究 CS 诱导的新机制 肺损伤，重点关注凝集素补体途径的哪些成员是诱导肺损伤所必需的 CS 期间肺部沉积、2 型肺泡上皮 (AT2) 细胞补体功能障碍和肺气肿 在目标 2 中，我们将研究补体调节剂衰变加速因子 (CD55) 是否存在。 需要防止凝集素补体沉积在 AT2 上，防止 AT2 细胞损伤、死亡和 在目标 3 中，我们提出了一种开发复合等离子体的转化方法。 补体活性评分，包括可以识别吸烟者的补体蛋白及其调节因子 我的建议解决了临床相关问题： 利用 AT2 细胞中的膜 CD55 表达和信号传导可以防止凝集素补体沉积 和激活，改善 CS 相关小鼠模型中 AT2 功能障碍和肺气肿的发展 我们的动物研究伴随着补体蛋白和调节剂的测量。 患有和不患有慢性阻塞性肺病的活跃吸烟者的血浆水平和活性使用 COPDGene 进行登记 多重平台，SomaScan 使用标准补体活性测试验证 SomaScan 测量， 总补体溶血活性 (CH50) 和 Wieslab 凝集素途径活性用于开发 “补体活性评分”我们将测试补体活性评分预测临床和临床的能力。 远端肺损伤进展的放射学参数。 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。