ARID1B基因变异通过Wnt/β-catenin信号通路导致矮小的分子机制研究

矮小是影响人口素质的重要因素之一，研究其病因及发病机制是关乎民生的重大问题。我们前期首次发现染色质重塑复合物(BAF复合物)中的ARID1B基因变异与综合征性及非综合征性矮小密切相关，但其致病机制不明。为此我们建立了arid1b knockdown斑马鱼模型，首次在动物体内证实ARID1B表达下调引起矮小；同时发现ARID1B表达下调异常激活Wnt/β-catenin信号通路。因此我们推测ARID1B基因变异可能通过影响其所在的BAF复合物的功能，异常激活Wnt/β-catenin信号通路，引起信号通路下游软骨细胞发育的关键基因表达下调，最终导致矮小。为验证该假设，本研究拟在斑马鱼及体外细胞系中探索ARID1B基因变异对BAF复合物、Wnt/β-catenin信号通路及软骨发育等方面的影响及其机制，并对所发现的重要靶点进行挽救实验，以明确ARIDB基因变异导致矮小的机制及可能的干预靶点。

As short stature has huge impact on the life quality of those individuals affected, the research on genetic etiologies and pathogenesis of short stature is a major issue of public health. In our previous studies, we found that variants in the ARID1B gene were associated with both syndromic and non-syndromic short stature. However, the pathogenic mechanisms have not been elucidated. In order to determine the actual outcomes of ARID1B variants in vivo and to research the pathogenesis of short stature, we firstly developed the arid1b knockdown zebrafish model. As a result, we found that arid1b knockdown led to short length and the Wnt/β-catenin pathway might be affected. According to the results of the zebrafish study and relevant literature information, we propose that ARID1B variants cause short stature via the Wnt/β-catenin pathway which is abnormally activated as a result of disrupted function of chromatin remodeling complex (BAF complex), leading to down-regulated expression of genes associated with cartilage development. In order to test the hypothesis, we intend to investigate not only the influence on the BAF complex and the Wnt/β-catenin pathway caused by ARID1B variants but also molecular mechanisms in the zebrafish model and cellular experiments. Moreover, rescue experiments will be performed aiming to discover new targets. The outcomes of the study will not only shed light on the underlying mechanism of short stature caused by ARID1B variants, but also provide new directions for the screening and discovery of novel therapeutic targets.