ARID1A调控Hedgehog信号通路的分子机制及意义研究

脊椎动物的骨发育受多条保守信号的精确调控，如Sonic Hedgehog（Shh）信号。大量的临床证据表明该信号的缺失或突变会导致骨发育的严重异常，但其致病分子机制不详。在长期探索Hh信号调控机制的研究过程中，我们发现ARID1A显著影响Shh信号的活性：敲降ARID1A激活Shh信号，而过表达ARID1A则抑制Shh信号；此外，ARID1A并不影响活化了的Shh诱导的下游信号。因此我们推测ARID1A可能通过调控Shh配体的加工和成熟而影响下游信号的传导。以上述结果为基础，本课题拟通过细胞模型和转基因小鼠模型，研究并阐明：1. ARID1A调控Shh的分子机制；2. ARID1A在Shh主导的肢芽发育中扮演的角色。本项研究不仅揭示Hh信号调控的新机制，而且提供骨发育调控的新理论，为临床相关疾病的防治提供靶点和参考。

The bone development of vertebrates is precisely regulated by a number of conservative signals, such as Sonic Hedgehog (Shh) signal. A large amount of clinical evidence indicates that the absence or mutation of this signal can cause severe abnormalities in bone development, but its pathogenic molecular mechanism remains unknown. In the long-term research process of exploring the regulation mechanism of Hh signal, we found that ARID1A significantly affects the activity of Shh signal: knockdown of ARID1A activates Shh signal, whereas overexpression of ARID1A inhibits Shh signal; in addition, ARID1A does not influence the downstream signal induced by activated Shh. Therefore, we speculate that ARID1A may affect downstream signal transduction by regulating the processing and maturation of Shh ligand. Based on the above results, this project intends to use cell models and transgenic mouse models to study and clarify: 1. The molecular mechanism of ARID1A regulating Shh; 2. The role of ARID1A in Shh-led limb bud development. This study not only reveals the new mechanism of Hh signal regulation, but also provides a new theory of bone development regulation, providing targets and references for the prevention and treatment of clinically related diseases.