先天性脊柱侧凸（congenital scoliosis, CS）是一种复杂的脊柱畸形。研究提示Tbx6（基因）与CS发病密切相关，宫内低氧（环境）亦起到关键作用，但二者关系尚不明确。申请人前期构建宫内低氧干扰Tbx6基因敲除小鼠的CS动物模型，初步证实miR-203-3p抑制Notch信号通路靶基因Hes1表达。由此提出假说，宫内低氧可通过非编码RNA调控机制，与Tbx6基因共同作用于Notch信号通路，影响正常体节发育导致CS的发生。为确证此假说，本课题将应用高通量基因芯片筛选宫内低氧相关miRNA、LncRNA，进一步采用RNA免疫共沉淀、原位杂交、荧光素酶报告基因等实验方法，从动物模型－细胞水平－病例多个层次，深入探讨宫内低氧与Tbx6基因共同作用导致CS发病相关的分子机制。目前国内外尚无CS基因－环境因素作用机制的文献报道，本研究将为CS的预防、早期诊治提供新思路和新策略。

Congenital scoliosis (CS) is a type of complicated spinal deformity. Previous studies showed that Tbx6 (genetic) may be closely related to the pathogenesis of CS, also intrauterine hypoxia (environmental) may play a key role in CS. However, interaction relationship between these two factors remains unknown. By constructing CS animal model of TBX6 gene knockout mice interfered by intrauterine hypoxia, the applicant initially verified that miR-203-3p could suppress the expression of target gene Hes1 via Notch signaling pathway. Therefore, we speculate that, through regulation mechanism of non-coding RNA, intrauterine hypoxia may work together with Tbx6 gene to affect normal development of somites which leads to CS via Notch signaling pathway. To bolster the hypothesis, this study will screen miRNA and LncRNA associated with regulation of intrauterine hypoxia through application of high-flux gene chip technique. Furthermore, the researchers will try to find and illuminate the molecular mechanism of CS pathogenesis induced by intrauterine hypoxia together with Tbx6 gene through experimental approaches such as RNA co-immunoprecipitation, RNA in-situ hybridization and luciferasereportergene, at multiple levels of animal model, cellular levels and clinical cases. At present there is no literature report of gene-environmental factor mechanism associated with CS around the world. This study will provide new ideas and new strategies for the prevention, early diagnosis and treatment of CS.