S1P/SREBP2介导自噬调控破骨细胞分化的机制研究

破骨细胞分化及功能的异常是导致骨质疏松等骨代谢疾病发生的重要原因，深入研究其分化调控机制对于发现新的治疗靶点具有重要意义。研究发现，S1P（Membrane-bound transcription factor site-1 protease）是调控骨骼发育的重要基因，但它在破骨细胞中的作用尚不清楚。申请人前期实验表明，S1P是破骨细胞分化的潜在调控因子：S1P在破骨细胞分化中表达显著升高，敲除S1P显著抑制破骨细胞分化；构建S1P条件敲除小鼠，发现其骨量明显增加。进一步结合生物信息学分析和文献调研，我们推测S1P/SREBP2信号轴通过调节自噬，影响破骨细胞分化及骨吸收功能。在本课题的研究中，申请人将利用S1P条件性敲除小鼠，结合临床样本，从分子、细胞和动物整体水平探索S1P的功能和自噬调控机制。从而为深入理解破骨细胞分化及相关骨代谢疾病的致病机理提供新的理论依据。

Dysfunction of osteoclast differentiation is an important cause of bone metabolic diseases including osteoporosis. In-depth study of the differentiation regulating mechanism has important implications for the discovery of novel therapeutic targets. Studies showed that S1P (Membrane-bound transcription factor site-1 protease) was an important gene for bone development, while its role in osteoclast remains unclear. Our results indicated S1P may be a potential regulator of osteoclastogenesis: the expression of S1P was significantly upregulated during osteoclastogenesis, while S1P knockout inhibited osteoclast formation; in addition, bone mass was increased in S1P conditional knockout mice. Based on bioinformatics analysis and literature researches, we hypothesized that S1P/SREBP2 signaling regulates osteoclast formation and resorption function through mediating autophagy. In the present study, we will use conditional knockout mice model and clinical samples to explore the function and mechanism of S1P on molecular, cellular and animal levels. Our study will provide new theoretical basis for further understanding the mechanism of osteoclastogenesis and bone metabolic diseases.