ROS-NLRP3-Caspase1信号通路介导的骨微血管内皮细胞焦亡在激素性股骨头坏死中的作用及机制研究

Vascular disorders caused by bone microvascular endothelial cells（BMECs）injury is one of the major reasons of glucocorticoid-induced osteonecrosis of the femoral head（ONFH）. In-depth understanding of the mechanism is of great importance to disease diagnosis and treatment. Our previous research data showed that GSDMD，a molecule marker of pyroptosis，as well as its upstream signaling pathway of ROS-NLRP3-Caspase1 increased significantly 24 hours after glucocorticoid injured BMECs, but the mechanism is still unclear. Accordingly, our project will firstly verify the relationship between pyroptosis and osteonecrosis of the femoral head through clinical specimens, then investigate the role and possible regulatory mechanism of“ROS-NLRP3-Caspase1” signal pathway in pyroptosis of BMECs. Finally, verify the regulatory mechanism by means of building the mouse experimental model of glucocorticoid-induced ONFH. The whole study will take advantage of measurements such as morphology, cytobiology, molecular biology and radiology. The whole study aims to provide new therapeutic targets and directions in the prevention and treatment of osteonecrosis of the femoral head from the prospective of endothelial cell injury.

骨微血管内皮细胞（BMECs）损伤引起股骨头血供障碍是糖皮质激素导致股骨头坏死的主要环节之一，深入理解其具体机制对于疾病的诊治具有重要意义。预实验中我们在体外水平构建激素损伤BMECs模型，发现BMECs损伤24小时后存在焦亡标志分子GSDMD及其上游信号通路ROS-NLRP3-Caspase1分子表达升高,其具体机制尚不清楚。本课题拟采用形态学、细胞生物学、分子生物学和影像学等多种手段，从临床标本中明确焦亡与激素性股骨头坏死的关系，通过构建糖皮质激素损伤BMECs模型探究“ROS-NLRP3-Caspase1”信号通路在焦亡参与激素损伤BMECs的作用及可能调控机制，最后通过构建小鼠激素性股骨头坏死动物模型对调控机制进行验证，以期从血管内皮损伤角度为激素性股骨头坏死的防治提供新的治疗靶点和思路。

骨微血管内皮细胞（BEMCs）损伤是糖皮质激素引起缺血性股骨头坏死发病机制的重要原因之一，具体机制的阐明对于疾病防治有重要意义。在本课题中，我们在细胞和动物水平对这一科学问题进行了系统性研究。研究结果表明，高浓度糖皮质激素诱导BMECs发生氧化应激，通过ROS激活依赖Caspase-1的经典途径，导致细胞焦亡发生。本研究对糖皮质激素损伤股骨头BMECs提供了直接的证据，为未来从血管内皮角度防治激素性股骨头坏死提供了新的思路。