mTORC1在软骨发生与发育过程中的作用及其机制

Chondrogenesis is a process of catileg formation. It involves the mesenchymal cell aggregation and chondrocyte differentiation, proliferation and hypertrophy. And, its regulation machanism has yet to clarify. Mammalian target of rapamycin complex 1 (mTORC1) is the central molecular which accepts intracellular and extracellular, signals, and regulates cell growth and metabolism. But its role and machanism in Chondrogenesis are still not clear. Our previous studies found that chondrocyte-specific TSC1 knock-out (mTORC1 excessively activated) mice occurred obvious the spine kyphosis and the thoracic malformations. The symptom was described as "instant noodles frizzled". At the same time, we also found that the secondary ossigication center of the tibial failed to form, upper section of the tibial generated a large number of hypertrophic chondrocytes, and no vascular ingrowth was shown. All of the above symptoms suggest that mTORC1 plays an important regulatory role in cartilage development. This research intends to do a study in finding the role and the machanisms in molecules, cells and the overall level that mTORC1 signal pathway plays in Chondrogenesis development, by using chondrocyte-specific TSC1 knock-out, Raptor(mTORC1 pathway inhibited) gene mice, and the gene knock-out chondrocytes model mentioned above. In order to add new contents to Chondrogenesis mechanism, and provide a theoretical basis for the future clinical treatment of cartilage regeneration .

软骨发生即为软骨形成的过程，涉及间充质细胞的聚集、软骨细胞的分化 、增值和肥大等，其调控机制目前仍未阐明。哺乳动物雷帕霉素靶蛋白复合物1(mTORC1)是接受细胞内外信号，调节细胞生长与代谢的中心分子，但它在软骨发生中的作用与机制不完全清楚。我们的前期研究发现，软骨细胞特异性敲除TSC1(mTORC1过度激活)小鼠发生脊柱明显后凸且胸廓发育畸形呈"方便面型卷曲"，同时胫骨次级骨化中心未能形成，上段有大量肥大软骨细胞，未见明显血管的长入，提示mTORC1在软骨发育中起重要调节作用。本项目拟通过软骨细胞特异性敲除TSC1 、Raptor (mTORC1通路被抑制)基因的小鼠以及上述基因敲除的软骨细胞等模型，在分子、细胞与整体水平研究mTORC1信号通路在软骨发生发育中的作用及机制，以期为软骨发生机制增加新内容，为今后软骨再生临床治疗提供新理论。