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通过调节肺纤维细胞中PKM替代拼接,SRSF7促进肺纤维化
Tongzhu Jin1,2, Huiying Gao1, Yuquan Wang1,3
1State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
Acta pharmaceutica Sinica. B
|July 14, 2025
概括
富含氨酸/氨酸的拼接因子7 (SRSF7) 通过改变细胞代谢来驱动异常性肺纤维化. 用洛米塔皮德向SRSF7显示出治疗这种肺部痕疾病的前景.
科学领域:
- 肺部医学 肺部医学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 异常性肺纤维化 (IPF) 涉及异常的伤口愈合和痕.
- 替代拼接 (AS) 在IPF病原体中的作用尚未完全理解.
- 异常纤维细胞激活是IPF的一个关键特征.
研究的目的:
- 调查氨酸/氨酸丰富的拼接因子7 (SRSF7) 在IPF中的作用.
- 阐明SRSF7对肺纤维化有所贡献的分子机制.
- 确定IPF的潜在治疗点.
主要方法:
- 在IPF患者衍生的纤维细胞和白素诱导的小鼠模型中量化SRSF7表达.
- 研究了SRSF7在人类胎儿肺纤维细胞和小鼠中的功能作用.
- 研究了SRSF7介导的替代拼接事件,重点是酸盐激酶 (PKM).
- 利用纤维细胞特异性SRSF7条件淘汰小鼠来评估其在体内的作用.
- 进行药物查以确定SRSF7调节器.
主要成果:
- 在IPF肺部和纤维细胞中,SRSF7的表达被上调.
- 在小鼠中SRSF7表达的升高导致了自发的膜原蛋白积累.
- SRSF7调节PKM的替代拼接,导致代谢失调和纤维细胞激活.
- 纤维细胞特异性SRSF7淘汰赋予了对白血素诱导的肺纤维化耐药性.
- 洛米塔皮德被确定为一种减轻实验性肺纤维化的SRSF7调节剂.
结论:
- 通过驱动纤维细胞代谢失调,SRSF7促进肺纤维化.
- 针对SRSF7代表了IPF的潜在治疗策略.
- 洛米塔皮德是治疗IPF的一种有前途的候选药物.
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