PDGF-BB/PI3K信号轴在高糖引发GSK-3β介导的成骨抑制过程中的调控机理

糖尿病患者骨缺损修复一直是临床治疗难点，干细胞功能下降导致的成骨抑制是主要制约因素。我们研究发现高糖引发的GSK-3β活性增加在此过程起重要作用；锂作为GSK-3β高效抑制剂，可有效逆转这一过程；PDGF-BB可在高糖环境下促进组织再生，但机制不明。因此我们提出假设：含锂mnHA/β-TCP缓释PDGF-BB可恢复干细胞功能，促进高糖状态骨缺损修复。本研究拟从分子、细胞和整体水平，利用锂mnHA/β-TCP、GSK-3β敲减及过表达小鼠干细胞、糖尿病小鼠颅骨缺损模型，以基因转染、活体成像、转录组测序等方法，探讨GSK-3β在高糖引发成骨抑制过程的具体作用及PDGF-BB/PI3K/GSK-3β信号轴的调控机理，明确锂mnHA/β-TCP缓释PDGF-BB对糖尿病小鼠干细胞功能及颅骨缺损修复的影响。本课题结果将揭示高糖环境下成骨抑制的具体机制及解决方案，为临床糖尿病患者骨缺损修复提供参考。

Bone defect repair in diabetic patients has always been a difficult clinical treatment, and osteogenesis inhibition caused by stem cell dysfunction is the main constraint factor. We found that the increase of GSK-3β activity induced by high glucose plays an important role in this process; lithium, as a highly effective inhibitor of GSK-3β, can effectively reverse this process; PDGF-BB can promote tissue regeneration in high glucose environment, but the mechanism is still unclear. Therefore, we hypothesized that lithium-containing mnHA/β-TCP scaffold with local sustained-releasing of PDGF-BB could restore the function of stem cells, and promote bone defect repair in high glucose state. In this study, first we will synthesize Li-mnHA/β-TCP scaffold, separately culture GSK-3β low-expression and over-expression mice stem cells, and establish diabetic mice cranial defect model. Then at the molecular, cellular and overall levels, by methods of gene transfection, in vivo imaging, transcriptome sequencing, et al, we will investigate the specific role of GSK-3β in the process of osteogenesis inhibition induced by high glucose and the regulatory mechanism of PDGF-BB/PI3K/GSK-3β signal axis, explore the effect of Li-mnHA/β-TCP with local sustained-releasing of PDGF-BB on the function of stem cells and the cranial defect repair of diabetic mice. The results of this study will reveal the specific mechanism and solutions of osteogenesis inhibition in high glucose environment, and provide references for the restoration of bone defects in clinical diabetic patients.