基于骨-血管-淋巴管多相网络调控的DNA自组装纳米结构修复早期激素性股骨头坏死

The clear pathogenesis of Steroid-induced necrosis of femoral head （SANFH）is still not revealed. A hypothesis "Bone - blood vessels - lymphatic polyphase network”: Immunology of bone plays an important role in the pathogenesis of SANFH , bone’s vasculitic immune mechanism and lymphatic dysmaturity may be an important cause of the unbalance homeostasis in immune microenvironments was first brought up by our team. By polyphase network regulation against SANFH, the “Multiple Interventions agsinst Pathogenesis” has been considered as a targeting and effective treatment strategy. From the above, polyphase network regulation and target therapy will be our cut-in point in this project. By utilizing MIF’s strong angiogenetic growth ability under the condition of hypoxia, glucocorticoid resistance vasculitic immune injury mechanism and VEGF-C controlling lymphatic hyperplasia, along with the efficient osteogenic differentiation of BMP-7 and cutting-edge self-assembly and nanotechnology, in this way, a multiple co-expression DNA nano-structure carrying BMP-7、MIF and VEGF-C can be engineered. The carrier’s repairing function will be evaluated in vivo and in vitro experiment. After the implementation of this project, the advantage of multidisciplinary cross will be certain, self-assembly of gene therapy provide a solid theoretical and experimental basis to early treatment of SANFH. Moreover, relevant clinical research can be carried out according to the findings of the project and the significant prospect can be seen in the future.

激素性股骨头坏死（SANFH）发病机制未明。我们提出“SANFH骨-血管-淋巴管多相网络调控假说”：骨免疫学在SANFH的发病中具有重要作用；骨血管炎性免疫机制和淋巴管成熟不良与发育障碍机制可能是SANFH免疫微环境稳态失衡的重要原因。针对上述机制，本课题将以多相网络调控及靶向治疗为切入点，利用MIF低氧缺氧环境下强大促血管化作用及其抵抗糖皮质激素血管炎性免疫损伤的机制以及VEGF-C调控淋巴管增生与成熟的效应，联合BMP-7高效的促成骨分化作用，创新性的通过DNA自组装纳米技术，构建携带BMP-7、MIF及VEGF-C多DNA共表达DNA纳米结构，综合评价该载体对SANFH的修复作用。本项目实施后必将利用多学科交叉的优势，在DNA自组装基因治疗层面对SANFH早期治疗提供崭新且坚实的理论和实验基础，并可根据本研究成果在多向网络调控层面开展实验性临床研究，具有极其重要的理论意义和应用前景。

激素性股骨头坏死(SANFH)发病机制未明。本课题提出“SANFH骨-血管-淋巴管多相网络调 控假说”:骨免疫学在SANFH的发病中具有重要作用;骨血管炎性免疫机制和淋巴管成熟不良 与发育障碍机制可能是SANFH免疫微环境稳态失衡的重要原因。针对上述机制，本课题以多相网络调控及靶向治疗为切入点，利用MIF低氧缺氧环境下强大促血管化作用及其抵抗糖皮质激素血管炎性免疫损伤的机制以及VEGF-C调控淋巴管增生与成熟的效应，联合BMP-7高效的促成骨分化作用，构建携带BMP-7、MIF及VEGF-C多DNA共表达 DNA外泌体结构，综合评价该载体对SANFH的修复作用。结果显示，淋巴管成熟不良与发育障碍是SANFH发病过程中的重要作用机制；血管内皮生长因C在骨淋巴管成熟发育过程中具有重要的调控作用，可明显改善骨小梁结构，增加骨密度；巨噬细胞移动抑制因子参与糖皮质激素性股骨头坏死发病的机制，MIF能够改善激素诱导的受损内皮细胞的形态与功能；BMP-7、MIF 及VEGF-C共表达纳米缓释外泌体对SANFH具有明确的修复作用。本项目利用多学科交叉的优势，在基因治疗层面对SANFH早期治疗提供崭新且坚实的理论和实验基础，具有极其重要的理论意义和应用前景。