PI3Kδ介导CCN1细胞特异性调控急性肺损伤的分子机制

急性肺损伤(ALI)病死率高，发病机制未阐明。我们前期研究提出了急性肺损伤气道局部发病机制的理论，并初步揭示ALI气道局部存在CCN1早期即刻炎症反应，并与PI3K形成正反馈调控。有研究表明CCN1具有细胞特异性多功能效应，即受体差异性与功能特异性，这种细胞特异性如何发挥对ALI的调控作用尚不清楚。我们假设：急性肺损伤早期触发时，气道局部存在CCN1受体差异性和功能特异性调控，CCN1-整合素受体-PI3Kδ信号通路介导ALI的发生发展。本项目通过基因敲除及转染技术构建不同细胞株和基因小鼠，研究ALI气道细胞结合CCN1的受体差异性和功能特异性，探讨CCN1细胞特异性对ALI的影响以及PI3Kδ的介导机制，阐明CCN1-整合素受体-PI3Kδ信号通路对ALI调控的分子机制，干预CCN1、整合素受体和PI3Kδ可能是未来靶向预防和治疗急性肺损伤的重要靶点。显示进一步临床转化的潜在前景。

Acute lung injury (ALI) is associated with high mortality. The pathogenesis of ALI remains to be fully elucidated. We have previously proposed a theory of local airway injury as the initial event in the pathogenesis of ALI. We have presented some initial evidence, that CCN family member 1 (CCN1) acts as an early immediate signal in local airway inflammation and form a positive feedback loop with the PI3K signal pathway. It has previously been reported that CCN1 exhibits cell-type specific pleiotropic effects owing to receptor diversity and function diversity. However, the regulatory mechanism underlying such cell-type specific pleiotropic effects is not clear. It is hypothesized that there exists CCN1 receptor as well as function diversity regulation in local airway at the onset of ALI, and the CCN1-Integrin-PIKδ signaling pathway participates in the development of ALI. The current projects aims at studying both the receptor and the function diversities of CCN1 in airway. We will use in vitro cell culture as well as genetically engineered mouse models to explore the mediator role of PIKδ signaling in cell-type specific pleiotropic effects of CCN1. Elucidation of the molecular mechanism of CCN1-Integrin-PIKδ signaling in ALI will help to design novel strategies targeting this pathway for therapeutic intervention.