FGF/FGFR2通过Wnt信号促进Apert综合征矢状缝异常软骨形成的作用与机制研究

矢状缝异常软骨形成是导致Apert综合征颅顶畸形的重要因素，弄清其病理发生的细胞及分子机制，对囟门早闭头颅畸形的治疗具有重要意义。文献及前期工作提示Apert中FGFR2可能通过增强Wnt信号促进矢状缝处的间充质干细胞（MSCs）向软骨细胞分化，导致异常软骨形成。本课题拟建立Apert小鼠中增强和敲除β-catenin的小鼠模型，对其头颅及颅缝形态进行分析，观察Wnt信号在Apert矢状缝异常软骨形成中的作用。结合间充质细胞系及分离的原代MSCs，对FGF/ FGFR2、Wnt信号进行干预，通过定向诱导分化，分析成骨、软骨细胞增生、分化、凋亡的影响，明确FGFR2调控Wnt信号在MSCs成骨、成软骨分化中的作用和机制。在上述工作基础上，用Apert小鼠进行体外及活体颅缝局部干预Wnt信号后对头颅形态进行分析，为开发通过干预Wnt信号来缓解Apert头颅畸形的生物治疗措施提供实验依据。

Ectopic cartilage formation in sagittal suture is the important factor to cause parietal deformity of Apert syndrome (AS). Thus, it has the important meaning for treatment of Apert syndrome to clarify the cellular and molecular mechanisms of the formation of ectopically cartilage. Literature and our previous work suggested that FGFR2 may enhance the Wnt signaling promotes the differentiate of mesenchymal stem cells (MSCs) into cartilage cells, which resulting in abnormal cartilage formation, in sagittal suture of AS. In this study we first establish mice model of overexpressed and knockout beta-catenin in Apert mice, and the skull and cranial suture morphology will be analyzed to observation the roles of Wnt signal in abnormal cartilage formation of Apert sagittal suture. Combined with analysis the effects of osteogenic, chondrogenic differentiation, proliferation, apoptosis of mesenchymal cell lines and primary MSCs came from AS mice by regulating the expression of FGFR2 and Wnt signaling. Then, based on the previous work，we will evaluate the effects of treatment of AS skull by intervention Wnt signal in local suture in vitro and in vivo. This study will exhibit experimental basis for treatment of deformity of Apert skull through biological treatment.