HIF1a正向调控SLIT3在BMP9促进MSCs成骨分化与血管形成中的作用与机制研究

BMP9是诱发成骨分化和血管形成的关键分子，探究其调控细节具有重要意义。课题组前期发现BMP9通过磷酸化Smad1/5/8上调HIF1α，HIF1α进一步正向调控Runx2，促进成骨与血管形成，显示HIF1α是成血管、成骨级联反应共同起始调节因子。而抑制Runx2不能完全抑制HIF1α的双向效应，提示该效应仍存在尚不清楚的分子机制。RNA测序发现BMP9和HIF1α显著上调神经轴突导向分子（SLIT3）表达，ChIP提示HIF1α与SLIT3启动子具有结合能力。因此，我们提出假说：HIF1α正向调控SLIT3，在协调BMP9促进成骨与血管形成效应中具有重要作用。本项目拟采用体内外实验，对HIF1α正向调控SLIT3的作用及其在调控BMP9促进MSCs成骨分化与血管形成的作用和分子机制进行深入研究。本研究不仅对于拓展骨发育生物学基础理论具有重要意义，而且对于治疗相关骨科疾病提供新的视角。

BMP9 is a key regulator that induces osteogenic differentiation and angiogenesis, with importance attached to exploring its regulatory functions. Our research team found that BMP9 up-regulates hypoxia-inducible factor 1α (HIF1α) through phosphorylation of Smad1/5/8, and HIF1α further directly regulates Runx2, resulting in bidirectional effect between osteogenesis and angiogenesis. These effects demonstrated that HIF1α is a co-initial regulator in the cascade responses between osteogenesis and angiogenesis. It was found that the bidirectional effect of HIF1α could not be completely inhibited after Runx2 was inhibited, which suggests that the molecular mechanism between osteogenesis and angiogenesis remains unclear. RNA sequencing revealed that BMP9 and HIF1α could significantly potentiate the expression of SLIT guidance ligand 3 (SLIT3), ChIP assay suggested that transcription factor HIF1α is capable of binding the promoter of SLIT3. Thus, we propose a hypothesis that the key regulator HIF1α positively regulates SLIT3 and plays an essential role in coordinating BMP9; to promote the coupling effects between osteogenesis and angiogenesis. This project intends to use in vivo and in vitro experiments to further study the effects of HIF1α in positively regulating SLIT3 and to investigate the possible molecular mechanism and signaling pathways, regulating the BMP9 induced coupling effects of osteoblastic differentiation and angiogenesis of MSCs. This project possesses great potential, not only for significantly expanding the basic theory of bone development and bone biology, but also in providing a new perspective on the treatment of related orthopedic diseases.