骨质疏松症是增龄相关的骨骼疾病，发病率高。老龄化过程中成骨能力绝对或相对不足是导致骨质疏松的主要原因。我们发现成骨细胞中缺失FGFR1（R1）的小鼠成年期骨量增加，成骨能力增强，提示R1是调控成骨细胞功能的重要分子。自噬与骨稳态维持密切相关，我们发现R1缺失的成骨细胞自噬水平升高，自噬相关蛋白ATG5表达上调，且成骨细胞敲除ATG5与敲除R1的小鼠骨骼表型刚好相反。据此，我们提出R1可能通过抑制ATG5调节自噬影响成骨细胞功能。本课题拟建立在成骨细胞中增强或敲除R1的小鼠模型，通过给予自噬激动剂或抑制剂，及在成骨细胞中同时敲除R1和ATG5，对比观察小鼠骨骼表型变化，并结合细胞和分子生物学实验研究R1是否经ATG5调节成骨细胞功能。本研究首次探讨了FGFs/FGFRs信号通过自噬调控成骨细胞功能的新机制，为从调节FGFs/FGFR1角度寻找促进骨形成、防治增龄性骨丢失的措施提供新的思路。

Osteoporosis is a kind of age-related disease with high morbidity. Impaired osteogenesis of osteoblasts is the main reason. Mice with deletion of FGFR1 in osteoblasts showed increased bone mass, bone formation and reduced bone resorption. FGFR1 is important for osteoblasts, but the mechanism is not clear. Autophagy is related to bone remodeling. We found that deletion of FGFR1 in osteoblasts led to increased autophagy level and increased expression of ATG5. And the bone phenotypes of mice with ATG5 deficiency in osteoblasts was just opposite to the phenotypes in FGFR1 mutant mice, which suggests that FGFR1 may regulate osteoblast autophagy through ATG5. In this study, we first treat mice with deleted or activated FGFR1 in osteoblasts with autophagy inhibitors or agonists, or generate mice with double deleting FGFR1 and ATG5 in osteoblasts. Then we plan to analyze the bone phenotype of these mice and use cell culture experiments to study the regulation of FGFR1 on ATG5. Our study will provide a new view to the role of FGFR1 in osteoblasts and the relationship autophagy.