FGF9条件性基因敲除对颅底软骨联合生长发育的影响和机制研究

Fibroblast growth factor 9 (FGF9) plays an important role in the growth and development of nervous, respiratory, reproductive and skeletal systems.Cranial base synchondrosis (CBS), on the other hand, influences growth and development of mid-face region, and is affected by orthopedic force employed against the maxillofacial region. Our preliminary study revealed a possible role of FGF9 in regulating chondrogenesis of CBS during growth and development,its exact functions and biological mechanisms, however, remain unclear. Based on the availability and supplies of the FGF9 LoxP and Col2A1 Cre mice, the aims of this study are (1)to create the specific mice breed with FGF9 conditional gene knocked out; (2)to examine temporal and spacial expression of FGF9 in CBS cartilage over various stages during pubertal growth, and (3)to explore the biological pathway and phynotypic mechanism of FGF9 in governing chondrogenic process in CBS and its transition to endochondral ossification. The significance of this study includes clarification of developmental traits of CBS, and a better understanding of its potential relevance with craniofacial developmental deformity and malocclusions.

成纤维细胞生长因子9(FGF9)在神经、呼吸、生殖和骨骼系统的生长发育中发挥重要作用。颅底软骨联合的生长发育状态与面中部畸形的形成密切相关，并受施加在颌面部矫形力的影响。课题组前期实验提示FGF9可能在颅底软骨联合的生长中起重要作用，但该因子在颅底软骨联合生长发育中的功能和相关调控机制尚未明确。在已获得FGF9 LoxP和软骨细胞Col2A1 Cre小鼠的基础上，本课题拟制备软骨细胞FGF9条件基因敲除小鼠，检测FGF9在不同发育阶段颅底软骨联合中的表达和定位，观察FGF9条件基因敲除对小鼠全身及颅底软骨联合生长发育的影响，探讨FGF9影响颅底软骨联合生长发育的分子生物学机制。本研究意义在于从基因水平探究颅底软骨联合成骨过程的生物学路径，初步阐明颅底软骨联合生长发育的机制，揭示颅底软骨联合与发育性疾病，特别是与颅颌面部发育畸形及错合畸形形成的潜在关系，为颅颌面部正畸矫形治疗提供理论依据。

成纤维细胞生长因子 9(FGF9)在神经、呼吸、生殖和骨骼系统的生长发育中发挥重要作用。颅底软骨联合的生长发育状态与面中部畸形的形成密切相关，并受施加在颌面部矫形力的影响。课题组前期实验提示 FGF9 可能在颅底软骨联合的生长中起重要作用，但该因子在颅底软骨联合生长发育中的功能和相关调控机制尚未明确。在已获得 FGF9 LoxP 和软骨细胞 Col2A1 Cre 小鼠的基础上，本课题拟制备软骨细胞 FGF9 条件基因敲除小鼠，检测FGF9 在不同发育阶段颅底软骨联合中的表达和定位，观察 FGF9 条件基因敲除对小鼠全身及颅底软骨联合生长发育的影响，探讨 FGF9 影响颅底软骨联合生长发育的分子生物学机制。本研究显示，与对照组小鼠相比，fgf9条件性基因敲除小鼠的外观和体重无差异，但其颅底的骨密度明显下降。软骨细胞分化相关因子，如II型胶原,X型胶原，Ihh，sox9等在fgf9条件性基因敲除小鼠颅底的表达均明显下降。本研究强烈提示FGF9可能在颅底的发育中发挥了重要作用。