Gab1介导宫内感染诱发支气管肺发育不良的分子机制研究

Bronchopulmonary dysplasia (BPD) is a severe sequel of premature infants. Multiple factors are concerned with the immature lung in the pathogenesis of the disease. Among them, intrauterine infection plays an important role.Currently little is known about the mechanism of intrauterine infection-induced BPD. Gab1, which is widely expressed, is the key molecule to mediate phosphorylation. Recent studies show that Gab1 is one of a major predisposing factors for asthma. Our previous study has showed Gab1 play an important role in the regulation of lung epithelial injury and fibrosis remodeling process. This study will build on Gab1 conditional knockout animal models (SP-C-rtTA / (tetO) 7-Cre/Gab1flox/flox) to clear the pathophysiological role of Gab1 in regulation the development of BPD. Currently transgenic animal model has been completed constructed. Preliminary data has showed that Gab1 deletion caused pulmonary surfactant disorder and thus increased the LPS-mediated inflammation and lung damage. Based on these basis, this research will knockout Gab1 in mouse embryonic offspring (E16.5-18.5) in the third trimester, establish intrauterine infection model (LPS and Poly-IC-induced intrauterine infection) to understand molecular mechanisms and physiological significance of Gab1 in regulation of alveolar dysplasia to provide a theoretical basis to identify the etiology of this disorder and help to treatment of BPD.

宫内感染是导致新生儿支气管肺发育不良(BPD)的重要因素，然而目前宫内感染诱发BPD机制知之甚少。Gab1是广泛表达的介导磷酸化信号调控的关键分子，最近遗传学研究提示gab1基因是哮喘主要易感因素之一。我们前期研究揭示Gab1在调控肺上皮损伤及纤维化重构进程中发挥重要作用。本研究将基于构建可诱导Gab1条件性敲除动物模型（SP-C-rtTA/(tetO)7-Cre/Gab1flox/flox）明确Gab1调控BPD的病理生理学意义，目前转基因动物已完成遗传学构建，初步数据显示Gab1缺失导致肺泡表面活性物质调控紊乱进而加重LPS介导炎症及肺功能损伤。基于上述基础，本研究计划在母鼠孕晚期诱导敲除子代胚胎鼠（E16.5-18.5）Gab1蛋白，建立母鼠宫内感染模型（LPS以及Poly-IC介导宫内感染），深入解析Gab1调控肺泡发育不良的生理学意义与分子机制，为BPD诊疗提供理论依据。

宫内感染是导致新生儿支气管肺发育不良(BPD)的重要因素，然而目前宫内感染诱发BPD机制知之甚少。Gab1是广泛表达的介导磷酸化信号调控的关键分子，最近遗传学研究提示gab1基因是哮喘主要易感因素之一。本研究构建可诱导Gab1条件性敲除动物模型（SP-C-rtT A/(tetO)7-Cre/Gab1flox/flox）明确Gab1调控BPD的病理生理学意义。研究发现,Gab1-/-小鼠肺切片的组织学分析显示无明显的病理改变或炎症。但Gab1缺失会导致肺泡表面活性物质调控紊乱进而加重LPS介导炎症及肺功能损伤。同时，通过研究DC细胞Gab1条件性敲除小鼠（CD11c-CreGab1flox/flox, C57B6/J）发现Gab1通过影响DC抗原递呈从而导致肺部炎症的分子机制。Gab1通过介导p115-RhoGEF与Rho的结合调节Rho的活化，正向调控DC的迁移过程，影响DC的抗原递呈过程。这为理解宫内感染导致的肺支气管发育不良提供了新的思路，同时提示Gab1可能是治疗BPD的潜在靶点。