骨髓基质细胞(BMSC)向成骨细胞分化减少，脂肪细胞分化增加是导致骨髓脂肪累积与骨质疏松的重要原因。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，但它在骨代谢调节与骨质疏松发生中的作用与机制不清楚。课题组前期研究发现mTORC1特异抑制剂雷帕霉素可抑制BMSC向脂肪细胞分化、促进其成骨分化，并抑制大鼠去卵巢引起的骨髓脂肪累积与骨丢失，提示mTORC1在骨代谢调节中起重要作用。本项目拟通过可诱导、成骨细胞与脂肪细胞特异性敲除TSC1(mTORC1过度激活)、Raptor（mTORC1通路被抑制)、PPAR-gamma基因的小鼠，以及敲除这些基因的BMSC、脂肪或成骨细胞等模型，研究mTORC1在决定BMSC分化方向与骨质疏松症发生中的作用，并探讨其细胞与分子机制，为骨代谢调节与mTORC1功能研究增加新内容，为骨质疏松防治提供新靶点。

It has been well established that accumulation of bone fat caused by increased adipogenesis and decreased osteoblasts differentiation from bone marrow stromal cells (BMSCs) plays important roles in pathogenesis of osteoporosis. Mammalian target of rapamycin complex 1 (mTORC1) integrates extra- and intra-cellular signals to regulate cell growth and metabolism. However, its roles and mechanisms in regulation of bone metabolism and pathogenesis of osteoporosis are not known. Our preliminary data demonstrate that mTORC1-sepcific inhibitor rapamycin inhibits adipogenesis and potentiates osteoblasts differentiation from BMSC. Most importantly, rapamycin reduced accumulation of bone fat and bone loss in ovariectomized rat. Using inducible, osteoblast- or adipocyte-specific deletion of TSC1 (mTORC1 overactivation), Raptor (inhibition of mTORC1) and PPAR-gamma mice and BMSC, adipocyte and osteoblasts as cellular and animal models, this project aims to investigate the roles of mTORC1 in regulation the differentiation potential of BMSC and pathogenesis at the molecular, cellular and animal levels. The molecular and cellular mechanisms in this process will be further explored. The project will identify novel function of mTORC1 and mechanisms for bone metabolism and provide new targets for prevention and treatment of osteoporosis.