骨桥蛋白在慢性阻塞性肺病急性发作期对PI3K-δ及IL-17F调控机理研究

Acute execerbation of chronic obstructive pulmonary disease (AECOPD) is an attack and worseness of airway inflammation and obstraction in the certain condition, while there is still no specific approach for early diagnosis and therapy, since the pathogenesis remains unclear. Our previous studies found a significant correlation between osteopontin (OPN) and AECOPD duration, by the screening with proteomics and clinical bioinformatics. The proposed study will further validate OPN specificity to AECOPD based on clinical informatics, as compared with patients with acute and chronic lung injury, inflammation, infection, fibrosis or cancer, as well as high-risk population like long-term smokers. We will establish AECOPD model in ADA-/-，OPN-/-，IL-17F-/- knockout mice, and validate if OPN is a mechanism-specific marker, regulated through PI3K signal pathway, leading to IL-17F-dominant inflammation and involving in the development of AECOPD. We will investigate the direct role of OPN in lung epithelial cells and IL-7-positive T cells, explore molecular mechanisms where OPN-dependent and -dominant factors will be defined, in order to discover OPN-related, new, AECOPD-specific target combination for early diagnosis and therapy for the disease as well as the relationship between PI3K-δ，OPN and IL-17F.

慢性阻塞性肺病急性发作(AECOPD)是一种呼吸道慢性炎症和阻塞在特定情况下突发和恶化，目前没有早期诊治的特异性方法。本课题前期用蛋白谱学和临床生物信息学方法筛选AECOPD患者血中蛋白的动态变化,发现骨桥蛋白(OPN)与AECOPD病程有明显关系。本课题将同时比较OPN在肺损伤、炎症、感染、纤维化和肺癌和吸烟者的水平,通过临床信息学评估OPN在AECOPD的特异性。应用ADA-/- 、OPN-/-及IL-17F-/-等基因敲除小鼠建立AECOPD疾病模型，评估OPN是否机理特异性因子,是否受PI3K-δ调控，并调控Ｔ细胞IL-17F主导的炎性反应，参与AECOPD发展过程。研究OPN对肺上皮细胞和IL-17T细胞的直接作用，明确分子机制和其中OPN依赖和主导因子，阐明PI3K-δ、OPN及IL-17F三者之间关系和作用，发现与OPN相关的、新的、AECOPD特异性的、早期诊治的联合靶点。

慢性阻塞性肺病急性发作(AECOPD)是一种呼吸道慢性炎症和阻塞在特定情况下突发和恶化，由于发病机制尚不明确,仍没有早期诊治的特异性方法。本课题前期用蛋白谱学和临床生物信息学方法筛选AECOPD患者血中蛋白的动态变化,发现骨桥蛋白(OPN)与AECOPD病程有明显关系。本课题将测量和比较OPN在其他肺病患者（急慢性肺损伤、感染、纤维化和肺癌）和高危人群（长期吸烟）的水平,通过临床信息学评估OPN在AECOPD的特异性。在ADA-/- OPN-/- IL-17F-/-小鼠建立COPD疾病模型，评估OPN是否机理特异性因子,受PI3K-δ表达调控，并进一步调控Ｔ细胞IL-17F主导的炎性反应，从而参与AECOPD发生发展过程。研究OPN对肺上皮细胞和IL-17F细胞的直接作用，明确PI3K-δ调控OPN及进一步调控IL-17F的分子机制和其中OPN依赖和主导因子，阐明PI3K-δ、OPN及IL-17F三者之间的关系及其在AECOPD中的地位和作用，寻找与OPN相关的、新的AECOPD早期诊治的联合靶点。