GLIS1调控SHH信号通路在轴前多指发生中的机制研究

轴前多指（PPD）是最常见的先天性四肢畸形疾病，亚洲人群的发生率为0.8-1.4‰，临床表现为拇指完全或部分重复。目前绝大多数PPD患者的遗传致病因素仍不清楚。我们的前期研究发现：GLIS1调控SHH信号，与PPD的发生密切相关；GLIS1低表达时，SHH表达升高，SHH下游靶基因PTCH1和GLI1表达上升，而SHH的转录抑制因子TWIST1表达下降；SHH与PPD的发生关系密切。因此，我们提出假说：GLIS1突变会导致PPD的发生。其具体机制可能是：在胚胎发育中，GLIS1调控肢芽轴前的SHH表达；GLIS1突变使GLIS1表达降低，SHH表达上升，细胞的增殖和迁移能力增加，导致PPD的发生。本项目拟建立PPD遗传标本库，构建GLIS1敲除小鼠模型和GLIS1低表达/点突变细胞模型，从群体-动物模型-细胞-分子层面探讨GLIS1突变导致PPD发生的分子机制。

Preaxial polydactyly (PPD) is a most common congenital limb malformation with an incidence of 0.8-1.4‰ in Asian, characterized by partial or entire repetition of thumbs. At present, the genetic pathogenic factors of the vast majority of PPD patients remain unknown. Our preliminary study shows: GLIS1 regulates SHH signal pathway, closely associated with PPD. Lower expression of GLIS1 can increase SHH, which up-regulate PTCH1 and GLI1, with down-expression of TWIST1. Hence, we hypothesized that GLIS1 mutation would lead to PPD. The possible mechanism is that during embryonic development, GLIS1 regulates SHH expression in anterior region of the limb bud, and GLIS1 mutation reduces GLIS1 expression and increases SHH expression, increasing cell proliferation and migration, leading to PPD. Here, we plan to build the genomic library of PPD patients, and construct the GLIS1 knock-out mice and GLIS1 lower expressing/point mutation cell lines, to investigate our hypothesis on population, model animal, cell and molecule levels.