牵张成骨是在临床广泛应用的外科治疗手段。我们前期研究发现应力刺激能够促进复层MSC成骨，但其分子机制尚未完全阐明。文献报道显示PI3K、Akt、mTOR和ERK等信号通路节点分子均参与应力刺激诱导新骨形成过程；PI3K-Akt-mTOR和ERK-Mnk1信号通路均能够调控eIF4F复合物活性；同时eIF4F复合物控制着多种蛋白分子的翻译起始过程，其中包括β-catenin、HIF-1α、VEGF、bFGF和MMP-9等在成骨过程中发挥关键作用的分子。因此，我们推测应力刺激能够通过调控eIF4F活性促进新骨形成。本项目拟使用单层和复层MSC作为研究对象，系统探讨应力刺激后eIF4F活性的变化以及eIF4F复合物下游分子在应力促进新骨形成过程中的作用，以期证实调控eIF4F复合物活性是机械信号转导通路的中心环节，从而阐明应力刺激促进新骨形成的分子机制，并为筛选调控新骨形成药物提供新的靶点。

Distraction osteogenesis is a widely used technique in surgery clinics. However, its molecular mechanism has not been fully uncovered yet. Substantial reports demonstrated that mechanical stress could activate several signaling molecules, such as PI3K, Akt, mTOR and ERK, and both PI3K-Akt-mTOR and ERK-Mnk1 pathways have been shown to be involved in regulation of eIF4F complex. Moreover, eIF4F complex controls the translation initiation step of many proteins. Among these proteins, β-catenin, HIF-1α, VEGF, bFGF and MMP-9 had been proved to play key roles in osteogenesis. All these evidence lead us to suppose that eIF4F complex may be of importance in mechanical stress induced osteogenesis. In this project, we will investigate the changes of eIF4F complex activity and function of eIF4F downstream molecules in the osteogenesis process induced by mechanical stress by using single-layered and multilayered mesenchymal stem cell as experimental subject. This project will provide evidence in confirming that eIF4F complex is a novel critical node in mechanical signal transduction network and uncovering an eIF4F-dependent pathway which is involved in mechanical stress induced osteogenesis. Furthermore, this project will help us in finding new drugable targets in promoting osteogenesis and shortening the lengthening time in distraction osteogenesis.

牵张成骨是在临床广泛应用的外科治疗手段。我们研究发现通过化学试剂模拟应力刺激能够促进复层MSC成骨，但其分子机制尚未完全阐明。文献报道显示PI3K、Akt、mTOR和ERK等信号通路节点分子均参与应力刺激诱导新骨形成过程；PI3K-Akt-mTOR和ERK-Mnk1信号通路均能够调控eIF4F复合物活性；同时eIF4F复合物控制着多种蛋白分子的翻译起始过程，其中包括β-catenin、HIF-1α、VEGF、bFGF和MMP-9等在成骨过程中发挥关键作用的分子。因此，我们推测应力刺激能够通过调控eIF4F活性促进新骨形成。本项目拟使用单层和复层MSC作为研究对象，系统探讨应力刺激后eIF4F活性的变化以及eIF4F复合物下游分子在应力促进新骨形成过程中的作用。实验结果表明，1）应力刺激能够通过同时激活PI3K-Akt-mTOR和MEK-ERK-Mnk1信号转导通路；2）激活PI3K-Akt-mTOR和MEK-ERK-Mnk1信号转导通路均能够上调eIF4F复合物活性；3）eIF4F复合物活性上调可以促进下游分子c-myc、HIF-1α、ODC、Bcl-2、Bcl-xL、Survivin、VEGF、bFGF、MMP-9等表达，促进细胞增殖、迁移和侵袭，抑制细胞凋亡，进而促进新骨形成。本项目不仅阐明应力刺激促进成骨的重要分子机制，同时为筛选调控新骨形成药物提供了新的靶点。