REDD1-mTOR/TXNIP信号调控内皮细胞糖代谢异常阻碍脑梗死后血管新生的研究

血管新生促进脑梗死后三级侧枝建立，对于拯救缺血半暗带和改善长期预后至关重要。脑梗死后虽有血管生成信号高表达，但新生血管仍然难以维持且逐渐消退，其机制尚未明确。我们前期发现REDD1介导内皮细胞糖代谢异常，与新生血管消退正相关，并根据前期预实验结果提出REDD1通过mTOR/TXNIP调控内皮糖代谢障碍阻碍脑梗死后血管新生的假说。本项目拟：①通过MOST血管重建、代谢组学、激光共聚焦等方法探讨脑梗死后REDD1信号与内皮细胞糖代谢异常、新生血管紊乱和渗漏的调控关系；②采用透射电镜、免疫共沉淀等手段阐明内皮细胞 REDD1信号双重调控 mTOR-PGC1-α和TXNIP-GLUT1信号途径,导致内皮糖代谢调节异常的分子机制；③通过PET灌注及代谢成像等途径，验证REDD1抑制对血运重建和临床预后的改善作用。本项目拟从内皮代谢调控新视角探索脑梗死后血管新生机制，为脑梗死急性期治疗提供新策略。

Angiogenesis promotes establishment of tertiary collateral circulation after stroke, which is essential to save ischemic penumbra and improve long-term prognosis. However, neovascularization is unsustainable and gradually regressed under high expression of pro-angiogenesis signal after stroke. We previously found that REDD1 mediated endothelial disorder of glucose metabolism, which is positively correlated with regression of neovascularization，and we proposed the hypothesis that REDD1-mTOR/TXNIP impedes post-stroke angiogenesis by disturbing endothelial glucose metabolism on the basis of preliminary experiment. This project aims at: 1) To investigate the regulatory relationship between REDD1, endothelial glucose metabolism, angiogenesis disorder after stroke by using MOST vascular reconstruction, metabolomics, laser confocal and so on. 2) To clarify the specific molecular mechanism that endothelial REDD1 signal dually regulated mTOR-PGC1-α and TXNIP-GLUT1 signaling pathway, thus promoting the disorder of endothelial glucose metabolism and angiogenesis. 3) To verify the improvement of REDD1 inhibition on revascularization and clinical prognosis by using PET perfusion and metabolic imaging. This project aims to explore post-stroke angiogenesis through novel perspective on endothelial glucose metabolism, thus providing effective targets and strategies for the treatment of ischemic stroke.