CCN1-PI3K即刻早期正反馈环调控急性肺损伤的分子机制研究

急性肺损伤(ALI)死亡率高、发病机制复杂,与肺内皮和上皮细胞、炎症细胞的激活及相互作用相关。我们前期研究证明了PI3K通路在ALI中起关键作用，PI3K抑制剂干预ALI发现气道局部使用效果更明显，但PI3K参与的具体机理尚不清楚。CCN1是炎症启动的基质蛋白也是炎症信号传递的初始者之一，并与PI3K形成正反馈信号环。本项目检测我们假设"局部CCN1-PI3K对话机制调控ALI的炎症，干预局部CCN1-PI3K的表达，调控其下游通路的瀑布效应及正反馈信号环，影响ALI的发生及进展"，探讨肺内皮、上皮细胞和白细胞在CCN1-PI3K信号中的角色。通过特异性细胞表达CCN1的转基因模型，使其在动物和细胞株中过表达或缺失表达，研究CCN1-PI3K环对ALI的影响。分析局部CCN1-PI3K正反馈通路在ALI中的作用和作为治疗ALI靶点的可能性。

Acute lung injury (ALI) has high mortality, with a complex pathogenesis, associated with activations of pulmonary endothelial and epithelial cells and inflammatory cells, Our previous studies found that PI3K-dominant signal pathway plays a critical role in ALI, evidenced by the topical therapeutic effects of PI3K inhibitors in the prevention of ALI, even though the exact mechanism of PI3K involvement remains unclear. CCN1 acts as an immediate and initial signal in inflammation and injury,as a positive feedback in the PI3K-dominant signal pathway. The proposed studies aim at testing our hypothesis that local CCN1-PI3K may be associated with the development of ALI, the local expression of CCN1-PI3K has the cascade effect on the regulation of its downstream pathway and the positive feedback signal rings. We also explore the role of lung cells and leukocyte cells in ALI development through transgenic models, neutrophils or endothelial cells with up-regulated expression or deletion of CCN1, respectively, to validate the role of CCN1-PI3K positive feedback pathway in ALI and potential for targeting therapies.