TBX6相关先天性脊柱侧凸胚胎发育模型的建立及分子机制研究

Congenital scoliosis (CS) is a kind of congenital vertebral malformation caused by abnormal growth of vertebral body during embryonic development. It can cause serious paralysis, which is one of the major diseases of the disabled teenager. In the previous study, our research group found for the first time that the complex genetic variation of TBX6 gene is one of the causes of CS, and has been independently verified by different populations in other groups. In this study, we established the TBX6-related congenital scoliosis mouse model, and confirmed that the TBX6 gene is highly pathogenic in different populations and different species.TBX6 gene is an important transcription factor in the formation of the embryo, we speculate that in the developing phase of embryonic somite, the pattern of TBX6 gene complex genetic pathogenesis in vertebral formation may contribute to the molecular mechanism of abnormal processes. To confirm this hypothesis, we employ the developmental mouse embryos model, from the insight of morphological development and transcriptional regulation, to comprehensively study the molecular regulation of TBX6 gene variation in the processes of somitogenesis. In conclusion, from the perspective of embryonic development, we will clarify the molecular mechanism of TBX6 gene variation leading to congenital scoliosis, and provide new ideas and theoretical bases for early intervention and treatment of this disease.

先天性脊柱侧凸(Congenital Scoliosis，CS)是一种在胚胎发育期，椎体发育异常所致先天性骨骼畸形疾病，严重时可致患者瘫痪，是造成青少年残疾的主要疾病之一。在前期研究中，本课题组首次发现TBX6基因复合遗传变异是导致CS的病因之一，并相继得到国外课题组不同人群的独立验证。本课题组进一步建立TBX6相关先天性脊柱侧凸小鼠模型，证实TBX6基因该致病模式在不同人群和不同物种间具有高度致病性；TBX6基因是胚胎形成的重要转录因子，我们推测在胚胎体节发育期，TBX6基因复合遗传致病模式在椎体形成中可能导致其分子调控机制异常。为证实这一假说，我们基于小鼠胚胎发育模型，从发育形态学及转录调控等层次，深入研究TBX6基因复合遗传变异所致体节分化异常的分子调控机制。本课题将从胚胎发育的角度，阐明TBX6基因变异导致先天性脊柱侧凸的分子机制，为该类疾病早期干预和治疗提供新思路和新的理论依据。

先天性脊柱侧凸(Congenital Scoliosis，CS)是一种在胚胎发育期，椎体发育异常所致先天性骨骼畸形疾病，严重时可致患者瘫痪，是造成青少年残疾的主要疾病之一。在前期研究中，本课题组首次发现TBX6基因复合遗传变异是导致CS的病因之一，并相继得到国外课题组不同人群的独立验证。本项目建立TBX6相关先天性脊柱侧凸胚胎发育模型，验证了其通过依赖基因剂量到导致先天性脊柱畸形的观点。本项目研究获得以下主要研究成果和重要意义：.（1）建立了TBX6相关先天性脊柱侧凸小鼠模型（TBX6mh/-），证实TBX6基因该致病模式在不同人群和不同物种间具有高度致病性；.（2）首次定义了一种全新的脊柱侧凸亚型（TACS），基于多元回归模型成功建立了TACScore预测系统来评估临床TACS的患病风险。.（3）通过回顾性研究证实TACScore应用于全外显子测试前的筛选测试之前时，是一种具有成本效益的工具。.（4）基于患者及小鼠模型发现TBX6是先天性肾脏和尿路畸形的遗传致病因素之一，TBX6的剂量不足可能是16p11.2微缺失综合征肾脏畸形的潜在诱因。.（5）扩大了TBX6致病基因的突变谱等位基因，提高了分子诊断检出率，提供了进一步的证据支持了CS的基因剂量依赖性遗传模型，以及完善了的临床分类。.（6）探索了单细胞转录组分析技术应用于TACS小鼠模型胚胎期细胞水平分子机制研究。