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S1PR1偏差激活通过保持内皮完整性来驱动内皮功能障碍相关的炎症性疾病的解决

Huaping Zheng¹, Jingjing Yu^1,2, Luhua Gao¹

¹Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.

Nature communications

|February 20, 2025

概括

一种新药,SAR247799,向内皮细胞中的基-1-酸盐受体1 (S1PR1),通过保护内皮屏障而不会引起免疫抑制来治疗炎症性肠病 (IBD).

科学领域:

生物化学生物化学
免疫学免疫学免疫学
药理学药理学是指药理学的学科.

背景情况:

氨酸-1-酸受体1 (S1PR1) 是炎症性肠病 (IBD) 治疗的目标.
激活S1PR1有助于免疫细胞从淋巴结退出,这可能导致免疫抑制.
在内皮细胞中S1PR1的精确信号通路及其治疗潜力仍然不完全理解.

研究的目的:

在IBD的背景下调查S1PR1在内皮细胞中的作用.
在IBD模型中探索Gi偏差S1PR1激动剂SAR247799的治疗疗效.
阐明Gi偏差S1PR1激动的结构基础.

主要方法:

对IBD患者内皮细胞中S1PR1表达的分析.
使用IBD的雄性小鼠和器官模型.
采用冷电子显微镜来确定S1PR1-Gi信号复合物的结构,使用SAR247799.

主要成果:

在IBD患者的内皮细胞中,S1PR1被上调.
基偏差激动剂SAR247799通过增强内皮屏障完整性来改善IBD病理.
SAR247799对内皮屏障的作用并没有阻止免疫细胞的退出.
低温电子显微镜结构揭示了SAR247799.9的结合和激活机制.

结论:

基基偏差的S1PR1激动症通过向内皮屏障功能,为IBD提供了治疗策略.
SAR247799显示出治疗与内皮功能障碍相关的炎症性疾病的潜力.
这项研究为治疗开发提供了对Gi偏差S1PR1激动剂的机制性见解.

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