新冠病毒所致ARDS治疗新靶点：cdc42信号通路在Spike蛋白感染后肺泡上皮细胞损伤修复中的作用及机制

新冠病毒所致ARDS死亡率高，寻找治疗靶点意义重大。SARS-CoV-2表面的Spike蛋白与ACE2受体结合，损伤肺泡上皮细胞，是ARDS的主要发病机制，而促进Ⅱ型肺泡上皮细胞损伤后增殖分化，修复受损的肺泡结构，是治疗ARDS的核心。项目组前期研究工作已证实cdc42对肺泡上皮细胞的损伤修复具有首要的调控作用，因此我们提出新冠病毒感染后，cdc42可促进Ⅱ型肺泡上皮细胞损伤后的增殖分化修复，从而减轻ARDS的假说。拟利用基因敲除等技术，构建在Ⅱ型肺泡上皮细胞上表达不同cdc42活性的小鼠和细胞模型，并构建表达Spike蛋白SARS-CoV-2假病毒，感染上述小鼠和细胞模型，探索Spike蛋白损伤后Ⅱ型肺泡上皮细胞增殖分化修复的情况和机制，以及cdc42基因在Ⅱ型肺泡上皮细胞损伤后增殖分化修复中的作用，为治疗新冠病毒所致肺损伤和ARDS,以及减轻新冠感染后肺纤维化提供研究思路和治疗靶点。

Acute Respiratory Distress Syndrome (ARDS) is a feared complication of COVID-19 caused by the novel coronavirus SARS-CoV-2 and a major cause of mortality. Finding a therapeutic target to prevent or blunt this syndrome resulting from this infection is thus of utmost importance. One of the SARS-CoV-2 surface proteins, called spike protein, binds the ACE2 receptor on lower respiratory epithelial cells, ultimately causing alveolar epithelial cell injury leading to ARDS. Promoting proliferation and differentiation of alveolar type II epithelial cells will lead to repair of the damaged alveolar structure and is at the core of effective treatment of ARDS. Our preliminary research shows that the Rho GTPase cdc42 plays a primary regulatory role in this process. We hypothesize that cdc42 can promote alveolar type II epithelial cell proliferation, differentiation, leading to repair after injury, thus reduce damage caused by ARDS. We plan to generate both a mouse and cell-culture based model, where alveolar type II epithelial cells express cdc42 at varying activity level utilizing gene knockout technology. We then plan to generate a SARS-CoV-2 pseudovirus, which expresses the viral spike glycoprotein, and would then use it to infect mice and cells in culture containing the cdc42-expressing type II alveolar epithelial cells. In this model we would be allowed to understand how the spike-protein-initiated viral attachment to respiratory epithelial cells leads to damage of type II alveolar epithelial cells and what the role of cdc42 is in its repair regulation via proliferation and differentiation. Ultimately, this study can thus lead to novel therapeutic targets for the treatment of pulmonary injury and ARDS caused by novel coronavirus, as well as for the alleviation of pulmonary fibrosis, a feared long-term complication leading to a reduction in mortality and morbidity.