SND1的转化调节在压力期间控制内皮质平衡
Zhenbo Han1, Gege Yan1, Jordan Jousma1
1Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA.
The Journal of clinical investigation
|February 3, 2025
概括
铁氨酸激酶抑制剂 (TKIs) 导致内皮压力. 我们发现,控制SND1 (葡萄球菌核酶和Tudor域含蛋白1) 的翻译可以防止TKI诱导的血管功能障碍.
科学领域:
- 心血管生物学 心血管生物学
- 分子瘤学分子瘤学
- 翻译医学是一种翻译医学.
背景情况:
- 氨酸激酶抑制剂 (TKIs) 是关键的癌症治疗方法,但可能导致心血管副作用.
- 内皮细胞经历TKIs的压力,影响血管健康.
- 在细胞应激期间,转化控制对基因表达调节至关重要.
研究的目的:
- 为了研究转化控制在内皮细胞的作用,在由sunitinib诱导的压力下.
- 为了确定特定的基因和途径参与sunitinib诱导的内皮功能障碍.
- 探索治疗策略,以减轻与TKI相关的血管毒性.
主要方法:
- 使用人类诱导的多能干细胞衍生的内皮细胞 (hiPSC-EC) 模型.
- 采用核糖体分析来分析翻译控制.
- 研究了mTORC1/4E-BP1通路和SND1基因表达.
- 在体中进行药物选和体外/体内验证.
主要成果:
- 苏尼提尼布治疗通过mTORC1/4E-BP1通路转化抑制了葡萄球菌核酶和图多域含蛋白1 (SND1).
- 抑制SND1会使内皮功能障碍恶化,而SND1过度表达则可以防止sunitinib的影响.
- SND1调节了UBE2N,它与RNF8/RNF168一起调节了DNA损伤的修复.
- 拉米普利尔,一种ACE抑制剂,可以防止sunitinib诱导的血管功能障碍,而不会影响抗癌疗效.
结论:
- 对SND1的转化控制是苏尼提尼布诱导的内皮功能障碍的一个关键机制.
- 针对SND1介导途径提供了一个潜在的治疗策略,以减少TKI心脏毒性.
- 拉米普利在预防苏尼提尼布诱导的血管损伤方面显示出有前途.
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