重度支气管肺发育不良的遗传学研究和相关通路基因的功能分析

支气管肺发育不良（BPD）是早产儿最常见的呼吸系统并发症，其中重度BPD的死亡率高，远期预后差。多项双胎研究显示，遗传因素参与了BPD的发生。文献报道和我们的前期研究提示，重度BPD患儿的基因组存在各种罕见变异，且个例BPD存在明显的基因变异的异质性和多基因参与的可能，针对BPD病例进行全基因组层面的深入研究有利于更全面地识别BPD的关键候选基因和信号通路。本课题拟扩大重度BPD核心家系量行全外显子组测序，结合转录组测序，寻找影响BPD发生的关键基因和信号通路；体外细胞水平对基因突变进行功能学验证；通过建立高氧暴露BPD大鼠模型和NGFR定点突变大鼠模型，研究PI3K-AKT-mTOR通路在BPD中的作用。本研究有助于识别出影响BPD发生发展的重要基因和通路，明确PI3K-AKT-mTOR通路在BPD中的作用，阐明重度BPD的遗传机制，为新防治手段的研发提供全新的思路。

Bronchopulmonary dysplasia (BPD) is the most common complication of premature birth, among which severe BPD is of high mortality and poor prognosis. Multiple twin studies showed genetic factor is involved in the pathogenesis of BPD. Based on previous reports in literatures and our recent research findings, there exist different kinds of rare mutations in the genomes of severe BPD infants， and the highly heterogeneity of mutations in individual BPD patient suggests the possibility of multiple gene involvement. Therefore in-depth investigation of the whole genome of BPD cases is crucial for the identification of key candidate genes and pathways involved in BPD. In this study, we plan to perform the whole exome sequencing on severe BPD family with larger sample size in search for candidate genes and pathways participating in BPD pathogenesis along with RNA-Seq. Function studies of novel variations will be performed in vitro. The role of PI3K-AKT-mTOR pathway in BPD pathogenesis will be investigated with the high oxygen exposed BPD rat model and NGFR targeted mutant rat model. This study will help to elucidate the genetic mechanism of severe BPD and provide new ideas for the development of novel interventional methods of BPD.