锚定蛋白Gab2调控肺损伤介导支气管肺发育不良的生理学意义和分子机制

Bronchopulmonary dysplasia (BPD) is still one of the main long term complications of preterm birth, and it is the most common chronic respiratory disease in infants. Due to advances in perinatal care and neonatal respiratory therapy, the survival of preterm infants is increased, but the incidence of BPD is also increased. The development of BPD is a multifactorial process with pathogenesis being linked to immature lung tissue, barotrauma and volutrauma resulting from mechanical ventilation, oxidant injury, and proinflammatory mediators. Inflammatory regulation may also have a role in the development of the new form. There is growing evidence that BPD results from an imbalance between proinflammatory and anti-inflammatory mechanisms, with a persistent imbalance that favors proinflammatory mechanisms. However, the molecular pathological mechanisms of BPD are not yet clear. The growth factor receptor-bound protein 2 (Grb2)-associated binder2 (Gab2) is a scaffolding/docking molecules, participating in multiple key intracellular signaling pathways, such as the growth factors fibroblast growth factors (FGFs), epidermal growth factor(EGF), which are associated with lung development. Gab2 is also an important inflammatory regulator. Our preliminary experiments data show that Gab2 participates in inflammatory cells transport mediated by lung injury, which prompt Gab2 may be a potential regulatory molecule involved in BPD pathophysiological process. This study will investigate the inflammatory effector cells (granulocytes, macrophages) transport in BPD models caused by intrauterine infection and hyperoxia on the basis of Gab2 Knockout mouse models. And then clear the role of Gab2 involving in the mechanism of BPD in lung dysplasia, mesenchymal pathology change, pulmonary fibrosis and pulmonary function loss. The results will help in-depth annotation of the pathogenesis of BPD and provide a new theoretical basis for clinical diagnosis and treatment.

支气管肺发育不良（BPD）是婴幼儿最常见的慢性肺疾病之一，严重影响患儿生存质量。一般认为早产儿肺发育不成熟、各种原发性及医源性肺损伤（如宫内感染、氧疗及机械通气等）导致的持续性肺部炎症反应可能是引起BPD的主要因素，然而分子机制尚未明确。锚定蛋白Gab2是肺发育依赖的多种生长因子(FGFs、EGF)的关键胞内信号调控分子，也是重要的炎症调控因子,我们预实验数据显示Gab2参与肺损伤介导炎症细胞转运过程，提示Gab2可能是参与BPD病理生理过程潜在的调控分子。本研究将主要基于Gab2基因敲除小鼠模型(Gab2 KO)研究Gab2调控由宫内感染以及高氧暴露等因素引起的BPD时主要炎症效应细胞（中性粒细胞、巨噬细胞）的转运机制，进而明确Gab2在参与BPD相关的早期肺发育不良、肺间质病理改变、肺纤维化及功能丧失的作用机制。该研究成果将有助于深入诠释BPD的发病机制，为临床诊疗提供新的理论依据。

支气管肺发育不良有由多种因素造成的慢性肺损害。多种生长因子信号与炎症反应引发的肺损伤参与支气管肺发育不良。支架蛋白Gabs是生长因子信号的重要下游分子，同时也参与细胞的炎症反应。哺乳动物有3个Gab同源蛋白。我们的研究发现，肺上皮细胞特异敲除Gab1的小鼠对LPS刺激更敏感，表现为更多的炎症细胞进入肺泡，诱导产生严重的肺纤维化。机制方面，Gab1参与上皮细胞合成与分泌表面蛋白。与Gab2敲除小鼠的预实验数据比较，我们的结果表明了Gab1与支气管肺发育不良的相关性更强。我们后续的研究将在Gab1的基础上开展宫内感染和高氧吸入对Gab1敲除子鼠的肺发育情况研究。