FGFR2通过自噬影响干细胞衰老在Apert综合征发病机制中的作用研究

Apert syndrome is a severe craniosynostosis caused by gain of function mutations in FGFR2. Recently it has been reported that stem cell population decrease can lead to craniosynostosis. We found that Apert mice are characterized with premature aging phenotype with diminished suture stem cells, which indicates that Apert syndrome may result from suture stem cells defects. Autophagy is crucial for maintaining the self-renewal of stem cells, and autophagy dysfunction in stem cells causes senescence. Our studies further showed defect autophagy in Apert mice. These results suggested that activation of FGFR2 may accelerate stem cell senescence by decreasing autophagic activity, which results in craniosynostosis. In this study, we will generate mouse models with Apert mutation alone or Apert with p53, p16, ATG5 or AKT1 deficiency. By analyzing the skull phenotypes of these mice， and using cell culture experiments to study the mechanism of the regulation of FGFR2 on autophagy and stem cell senescence. Finally, we will test autophagy modulation and anti-aging drugs for their effect on the abnormal skull development in Apert mice. This study will deepen our understanding of the mechanism of Apert syndrome and skull development in aspect of autophagy and stem cell senescence, and provide experimental basis for development of clinical treatment for Apert syndrome and other craniosynostoses.

Apert 综合征（AS）是由 FGFR2功能增强突变所致颅缝早闭（CS），但机制不完全明确。新近研究发现颅缝间充质干细胞（MSCs）减少可以导致CS。我们发现AS小鼠出现早衰表型，其颅缝MSCs减少，提示AS可能是由MSCs衰老、减少引起，但机制不清。自噬在干细胞自我更新中发挥重要作用，自噬降低可引起干细胞衰老。进一步研究发现，AS小鼠自噬水平明显降低。据此，我们认为FGFR2可能通过抑制自噬促进颅缝MSCs衰老，从而导致CS，但具体机制不清。本课题拟建立遗传修饰p53、p16、ATG5或AKT1等衰老、自噬相关基因的AS小鼠，通过对比观察小鼠头颅畸形及颅缝MSCs的自噬、衰老情况，结合细胞和分子实验，明确自噬和干细胞衰老在AS发生中的作用并探讨相关机制。最后，将观察调节自噬、抗衰老药物对AS小鼠颅骨畸形的缓解作用。本题将深化对颅骨发育及AS发生机制的认识，为研发AS治疗措施提供依据。

Apert综合征是由FGFR2功能增强突变所致囟门早闭，但机制不完全明确。本题旨在利用小鼠模型研究成纤维细胞生长因子受体2在Apert综合征发生中的作用及机制，并探讨潜在的生物治疗措施。我们的研究发现FGFR2在颅缝间充质处表达，并且FGFR2阳性细胞表达颅缝干细胞相关Marker； FGFR2功能增强可负向调节自噬，促进颅缝MSCs的衰老发生，导致其成骨能力减弱；发现FGFR2可通过与ATG5 复合体相互作用，降低ATG12-ATG5 复合体蛋白水平和其下游信号分子PI3K/AKT 参与了对自噬的调控作用，并进而导致线粒体功能障碍，引起颅缝MSCs 衰老的发生；初步发现调节自噬、延缓干细胞衰老药物对FGFR2功能增强所致颅骨MSCs衰老有一定的缓解作用。本题将深化对颅骨发育及Apert综合征发生机制的认识，为研发相关治疗措施提供依据。