FGFR3在调节生长板软骨发育及软骨瘤样发育畸形中作用与机制研究

调节骨发育分子异常可导致多种类型发育相关性骨病包括骨软骨瘤（OCM）样畸形。OCM的发生机制不完全明确。成纤维细胞生长因子受体3（FGFR3）抑制骨发育。我们发现敲除FGFR3可引起OCM，但详细分子细胞机制不清楚，比如OCM 的细胞来源？为何FGFR3嵌合小鼠比全敲除小鼠更易发生OCM? SHP2、MAPK、PI-3K/AKT等FGFR3相关信号在OCM发生中的作用等。 我们将以多种谱系特异表达及基于新理念自建的新型Cre小鼠与FGFR3、SHP2、ERK1/2、AKT等基因修饰小鼠为主要研究对象，综合应用谱系示踪、活体影像、骨培养及相关分子细胞、病理技术，探讨OCM的细胞来源及嵌合生长机制，并深入研究FGFR3对SHP2、MAPK、PI-3K/AKT的调节作用，及这些分子在FGFR3调节软骨发育及突变后所致骨骼发育异常，尤其是OCM发生中的作用，为探讨相关干预措施提供实验依据。

The abnormalities in genes regulating skeleton development will lead to a variety of diseases with maldeveloped skeleton including osteochondroma and enchondroma (OCM ). The mechanism for pathogenesis of OCM is not clarified. FGFR3 is a negative regulator of skeleton development. Gain of function mutation of FGFR3 cause achondroplasia. We recently found that knock out of FGFR3 in collagen II expressing cells caused OCM. Although enhanced IHH activity is involved in OCM, the mechanisms remain largely unclear. Based on our data, we raise these questions. Where the OCM comes from? Why conditional FGFR3 knock out leads to higher incidence of OCM? The role of SHP2, MAPK and PI-3K/AKT pathway in the regulation of skeleton development and prevention of OCM by FGFR3? In this study, we will, using a variety of Cre mice including those we generated with novel strategy and mice with genetic modification of FGFR3, SHP2, ERK1/2, AKT, study the cellular origin of OCM, the mechanism for the higher occurrence of OCM in chimera mice, and the role of SHP2, MAPK and AKT in the FGFR3 mutations related skeleton maldevelopment including OCM. Especially, we will study the mechanism for the down-regulation of AKT activity by FGFR3. These studies will provide experimental data for the development of potential preventive and therapeutic approaches for these skeleton maldevelopment.