取决于DNA的蛋白激酶催化子单元 防止视网膜色素上皮细胞中的铁亡
Xueying Wang1, Xi Wang1, Zhenzhen Zhao1
1Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, School of Medicine, Tongji University, Shanghai, China.
Investigative ophthalmology & visual science
|January 22, 2025
概括
取决于DNA的蛋白激酶催化子单元 (DNA-PKcs) 激活通过防止DNA损伤,保护视网膜色素上皮细胞免受铁亡. 这种激酶是RPE细胞铁灭的潜在治疗标.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 眼科医生 眼科 眼科
背景情况:
- 铁亡是一种受调节的细胞死亡形式,涉及依赖铁的脂质过氧化.
- 视网膜色素上皮细胞 (RPE) 对于视网膜健康至关重要,容易发生铁亡.
- 了解RPE细胞中铁亡的分子机制对于治疗视网膜疾病至关重要.
研究的目的:
- 调查DNA损伤反应 (DDR) 激酶在RPE细胞铁亡中的作用.
- 为了确定激活激酶对RPE细胞中铁亡的调节作用.
- 探索抑制RPE细胞铁灭的潜在治疗点.
主要方法:
- 在使用erastin的各种RPE细胞模型 (iRPE,hUCMSCs,iPSC-RPE) 中诱导了ferroptosis.
- 使用CCK8试验评估了细胞活力,并通过Calcein/PI染色检测出ferroptosis.
- 通过免疫染色和西式涂抹分析了DNA损伤标记物 (γ-H2AX,8-oxoG) 和激酶酸化 (DNA-PKcs,ERK1/2).
- 使用BODIPY581/591-C11染色方法量化了脂质过氧化.
主要成果:
- 诱导的RPE (iRPE) 细胞显示出比人类带介质干细胞 (hUCMSCs) 更大的铁灭抵抗力.
- 埃拉斯诱导的铁灭症在iRPE细胞中引发了快速的DNA-PKcs酸化,表明它具有保护作用.
- 抑制DNA-PKcs酸化加剧了铁亡,而DNA-PKcs抑制了铁亡早期的ERK1/2酸化.
- 这些发现与诱导多能干细胞衍生的RPE (iPSC-RPE) 细胞一致.
结论:
- 在RPE细胞铁灭过程中,DNA损伤反应激酶DNA-PKcs被激活,并具有保护作用.
- DNA-PKcs代表了一个新的治疗点,用于调节RPE细胞中的ferroptosis.
- 这项研究提供了抑制RPE细胞中铁亡的新策略,这与视网膜疾病治疗有关.
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