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空间蛋白质组学确定了JAKi作为致命皮肤疾病的治疗方法

Thierry M Nordmann^1,2,3, Holly Anderton^4,5, Akito Hasegawa⁶

¹Department of Proteomics and Signal Transduction; Max Planck Institute of Biochemistry, Martinsried, Germany. nordmann@biochem.mpg.de.

|October 16, 2024

概括

毒性表皮消亡 (TEN) 是一种严重的药物反应. 这项研究确定了JAK/ STAT和干扰素途径作为关键驱动因素,表明JAK抑制剂 (JAKi) 对TEN患者提供潜在的治疗疗法.

科学领域:

皮肤病学和免疫学
分子和细胞生物学
药理学

背景情况:

毒性表皮解剖 (TEN) 是一种危及生命的药物诱导的皮肤反应,其分子驱动因素未知,并且没有有效的治疗方法.
了解TEN的细胞和分子机制对于开发向疗法至关重要.

研究的目的:

使用深度视觉蛋白质学系统地绘制TEN中的分子变化.
确定TEN治疗的潜在目标.

主要方法:

在药物反应患者的皮肤活检中使用深度视觉蛋白质组学.
在角质细胞和免疫细胞中量化超过5000种蛋白质.
在TEN模型和患者治疗中使用JAK抑制剂 (托法西提尼布,巴里西提尼布,阿布罗西提尼布) 的体外和体内实验.

主要成果:

在TEN皮肤中丰富I/II型干扰素特征和化STAT1激活.
在实验室中,JAK抑制剂降低了角质细胞的细胞毒性,并在小鼠模型中改善了疾病的严重程度.
在七名TEN患者中使用JAK抑制剂显示出安全性,快速复上皮化和恢复.

结论:

已确定JAK/STAT和干扰素信号通路是TEN的主要致病驱动因素.
针对性的Janus激酶抑制剂 (JAKi) 在治疗TEN方面具有显著的治疗潜力.

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相关概念视频

The JAK-STAT Signaling Pathway

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...