FGFR3突变（G382D）介导细胞自噬在软骨细胞功能及其在软骨发育低下中的作用机制研究

成纤维细胞生长因子受体3（FGFR3）突变是导致软骨发育不全综合征（CHD）的重要因素。然而FGFR3突变激活下游信号通路致CHD的分子机制未完全阐明。课题组已收集40个CHD家系，并在国际上首次揭示FGFR3突变（G382D）可引起软骨发育低下（HCH）。我们前期研究发现携带G382D突变的软骨细胞ATDC5中，MEK/ERK信号通路被激活而细胞自噬受阻，提示FGFR3突变可能经MEK/ERK信号通路抑制细胞自噬而导致HCH。为验证该假设，本项目拟研究G382D突变对软骨细胞增殖分化和凋亡的影响，并通过CRISPR-Cas9技术构建FGFR3基因定点突变小鼠模型，首次将该突变引入小鼠，通过蛋白组学分析，识别FGFR3下游新型效应分子，从细胞自噬这一全新角度，在分子、细胞和动物三个水平，体外和体内结合，明确FGFR3在骨生长中的作用及其调控途径和关键分子，为制订HCH防治策略提供新思路。

Fibroblast growth factor receptor 3 (FGFR3) is an important gene responsible for chondrodysplasia syndrome (CHD). However, the molecular mechanism by which FGFR3 mutation activates the downstream signaling pathway leading to CHD has not been fully elucidated. We have collected 40 CHD pedigrees and have shown for the first time that FGFR3 mutation (G382D) can cause hypochondroplasia (HCH). Our previous study found that in chondrocytes ATDC5 carrying G382D mutation, MEK/ERK signaling pathway was activated and autophagy was blocked. It is suggested that FGFR3 mutation may inhibit autophagy through MEK/ERK signaling pathway and lead to HCH. To test this hypothesis, this project intends to study the effects of FGFR3 mutation (G382D) on chondrocyte proliferation, differentiation and apoptosis; and firstly introduce the mutation into the mice by generating a mouse model carrying a defined point mutation of FGFR3 via CRISPR-Cas9 system, and identify novel effector molecules downstream of FGFR3 through proteomic analysis. From the perspective of autophagy, this study will clarify the role of FGFR3 in bone growth and its regulatory pathways and key molecules at the molecular, cellular and animal levels, and further provide new evidence for HCH prevention and treatment strategies.