BMP与mTOR信号间对话影响成骨分化的机制研究

骨再生是一个复杂且精细的生理过程。成骨分化过程中细胞信号间的对话（crosstalk）机制是骨细胞生物学领域内重要的基础科学问题。文献报道mTOR信号通路促进成骨分化的研究结果存在较大争议，同时关于BMP和mTOR信号通路间对话的机制尚未阐明。本课题组前期研究发现，在成骨细胞中，早期mTORC1的激活有利于成骨细胞增殖以及成熟，然而在分化后期则抑制骨重塑。由此我们提出科学假设：mTOR信号通路对成骨分化的影响依赖于严格的时序动态调控机制；BMP和mTOR信号通路间对话可协同促进骨再生。本项目拟通过对成骨分化细胞谱系决定过程中涉及的脂肪间充质干细胞、成骨前体细胞以及成骨细胞的系统研究，明确mTORC1活性时序动态调控的机制；深入探究BMP和mTOR信号间对话的分子机制，明确关键节点分子。研究结果可望为BMP2联合小分子药物促进骨再生的临床应用提供理论依据，为临床骨缺损治疗提供新的思路。

Bone regeneration is a complex and delicate physiological process. The mechanism of signaling crosstalk during osteogenic differentiation is an important basic scientific issue in the field of bone cell biology. In the literature, researchers are debating the results of the mTOR signaling pathway promoting osteogenic differentiation, and the mechanism of the crosstalk between BMP and mTOR signaling pathways remains unclarified. Our previous study found that in osteoblasts, the activation of mTORC1 in the early stage is beneficial to their proliferation and maturation, while in the late stage of differentiation, it inhibits bone remodeling. Therefore, we propose a scientific hypothesis: the effect of the mTOR signaling pathway on osteogenic differentiation depends strictly on a temporally dynamic regulation mechanism, and the crosstalk between BMP and mTOR signaling pathways can synergistically promote bone regeneration. In this project, we aim to study the adipose-derived mesenchymal stem cells, preosteoblasts and osteoblasts involved in the process of osteoblastic lineage, to unravel the mechanism of temporally dynamic regulation of mTORC1 activity; to further explore the molecular mechanism of the crosstalk between BMP and mTOR signaling pathways, and to identify the key molecules. The results are expected to provide a theoretical basis for the clinical application of BMP2 combined with small molecular drugs to promote bone regeneration and provide new treatment strategy for clinical bone defects.