Rab26介导的受体失衡调控肺微血管内皮屏障损伤的作用及机制

It is well known that the damaged lung microvascular endothelial cells (PMECs) and endothelial barrier provoke acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We demonstrated that toll-like receptor (TLR4) and β-adrenergic receptor (β2-AR), respectively, had an important regulation in the injury PMECs. Small G protein Rab26 could control vesicular transport of β2-AR in HEK293T. Scientific hypothesis in this project: To maintain the balance between TLR4 and β2-AR -mediated by Rab26, and normal signal of GLI pathway in PMECs, could prevent endothelial barrier injury and the generation of ALI. Some kinds of methods will be applied here, including ligand saturation, Rab26 siRNA/plasmid transfection, Rab26-/- transgenic mice, TLR4-/- or/and β2-AR-/- knockout mice and so on. To investigate the protection of balance between TLR4 and β2-AR in PMECs injury, the signal mechanism of hedgehog/GLI from Rab26 mediated-damage of PMECs and endothelial barrier, and the molecular mechanism of endothelial barrier destruction. To explore the mechanism of the imbalance between TLR4- and β2-AR-mediated by Rab26, and of abnormality about the receptor transport in vesicular transport and their cascade signal pathway in PMECs and endothelial barrier injury. These will provide the new strategy and key target for prevention and treatment of ALI/ARDS.

肺微血管内皮细胞（PMECs）及屏障损伤是导致急性肺损伤（ALI）/ARDS的首要环节。我们研究表明TLR4及β-AR受体各自在PMECs损伤中发挥关键调节作用，而Rab26控制其胞内转运通路。据此提出：Rab26介导的受体平衡及关联的GLI信号畅通，可防治肺内皮屏障损伤及ALI发生。本项目应用配体饱和、Rab26 siRNA、质粒转染等技术，Rab26转基因鼠，TLR4-/-及β2-AR-/-基因敲除鼠等，研究Rab26调节两种受体失衡在PMECs损伤中的作用及囊泡运输进程，Rab26调节PMECs及内皮屏障损伤的关键信号通路Hedgehog/Gli机制，内毒素刺激PMECs的级联信号紊乱诱发连接分子occludin损坏，并导致内皮屏障损伤的分子机制，进而阐明Rab26调控TLR4及β-AR受体稳态在肺内皮屏障损伤及ALI的重要价值，为ALI/ARDS防治提供关键靶位和新策略。

肺微血管内皮细胞(PMECs)及屏障损伤是导致急性肺损伤(ALI)/ARDS 的首 要环节。我们研究表明 TLR4 及β-AR 受体各自在 PMECs 损伤中发挥关键调节作用，而 Rab26 控制其胞内转运通路。据此提出:Rab26 介导的受体平衡及关联的 GLI 信号畅通，可防治肺内皮屏障损伤及 ALI 发生。本项目应用Rab26 siRNA、质粒转染、Rab26基因敲除鼠等，研究 Rab26 调节两种受体失衡在 PMECs 损伤 中的作用及囊泡运输进程，Rab26 调节 PMECs 及内皮屏障损伤的关键信号通路 Hedgehog/Gli 机制，内毒素刺激 PMECs 的级联信号紊乱诱发连接分子VE-cadherin 损坏，并导致内皮屏障损 伤的分子机制，进而阐明 Rab26 调控 TLR4 及β-AR 受体稳态在肺内皮屏障损伤及 ALI 的重要 价值，为 ALI/ARDS 防治提供关键靶位和新策略。