构建SDPR转基因和敲除小鼠模型，研究SDPR在造血干细胞衰老中的调控机制

Hematopoietic stem cells (HSCs) have the abiliy to reconsduct hematopoiesis and immune system and they are important resource for tissue repair and regeneration. Mounting evidence suggested that decline of functional stem cells is a central player during the aging process. While a great deal of attention has focused on cell-intrinsic checkpoints and cell-extrinsic alterations of stem cells, relatively little research has focused on how the subcellular structure and composition of the cell membrane influences stem cell activities. SDPR is required for caveolae fomation, which is the regulation center for cell signaling. We showed that overexpression of SDPR induced features characteristic of cellular senescence in human fibroblast cells. And the SDPR transgenic mice showed the aging of HSCs, however the function and regulation mechanism of SDPR in HSCs self-renewing, differentiation,apoptosis and senescence remains unknown. In this project, we firstly will estabilish SDPR transgenic and knockout mice to investigate the function of SPDR in the regulation of HSCs and organs aging. Secondly, we will determine the signal pathway of SDPR indued HSCs aging, maybe incuding: p53, p16,Wnt and Bcl2 signal pathway. Thirdly, we will explore the the upregulator of caveolea. Our project will clarify the regulatory mechanism of HSCs aging through the interaction of SDPR and caveolae.

造血干细胞具有重建造血和免疫系统的能力，是组织器官维持和再生的重要因素，并在机体衰老进程中起着关键作用。骨髓微环境中的信号通过细胞膜进入造血干细胞内进而调节衰老相关的信号通路。SDPR是干细胞膜上胞膜窖结构的重要调节元件，胞膜窖是微环境与细胞内信号网络相互作用的关键节点。我们前期研究显示，过表达SDPR诱导细胞衰老，SDPR转基因小鼠呈现造血干细胞衰老的表型，但是SDPR如何与胞膜窖复合体相互结合，调节不同的信号通路，诱导造血干细胞进入不同状态还未有研究。本项目通过构建SDPR转基因小鼠和敲除小鼠模型，从正反两方面阐明SDPR在调节造血干细胞自我更新、分化、凋亡和衰老及在机体衰老的作用；明确SDPR诱导造血干细胞衰老的p53，p16，Wnt，Bcl2信号通路的激活状态；探索SDPR诱导造血干细胞衰老的上游细胞因子，最终解决SDPR与胞膜窖蛋白复合体相互作用进而调控干细胞衰老的科学问题。

造血干细胞具有重建造血和免疫系统的能力，是组织器官维持和再生的重要因素，并在机体衰老进程中起着关键作用。骨髓微环境中的信号通过细胞膜进入造血干细胞内进而调节衰老相关的信号通路。SDPR是干细胞膜上胞膜窖结构的重要调节元件，胞膜窖是微环境与细胞内信号网络相互作用的关键节点。本项目构建了SDPR转基因和基因敲除小鼠，在在机体水平、组织器官水平、造血干细胞水平和分子水平研究SDPR对于造血干细胞及机体衰老的作用。结果表明，SDPR转基因小鼠造血干细胞数量增加，淋系分化减少，髓系分化增加，呈现造血干细胞衰老的表型。进一步研究发现SDPR过表达之后会激活caveolin-1 /p53通路诱导造血干细胞的衰老。而SDPR敲除小鼠造血干细胞数量减少，髓系细胞和淋系细胞减少，造血干细胞激活MAPK通路诱导造血干细胞进入快速激活状态。因此SDPR在造血干细胞静息、增殖、凋亡和衰老不同命运调节中有着重要的作用，明确其上下游的信号通路，可以为造血干细胞衰老的分子机制提供直接的实验数据，对研究其他组织干细胞维持稳态具有重要的提示作用。同时SDPR转基因及基因敲除小鼠可以为研究SDPR和胞膜窖在生理和病理状态下的功能提供动物模型。