在TGF-β治疗的肺纤维细胞中,ATF4和mTOR调节代谢重编程
Kun Woo D Shin1, M Volkan Atalay2, Rengul Cetin-Atalay1
1Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL 60637.
bioRxiv : the preprint server for biology
|June 25, 2024
概括
异形性肺纤维化涉及纤维细胞代谢重编程. 这项研究揭示了激活转录因子4 (ATF4) 和机械点拉巴胺复合物1 (mTOR) 调节关键代谢通路,为纤维化提供潜在的治疗点.
科学领域:
- 细胞代谢的细胞代谢.
- 纤维性疾病 纤维性疾病
- 分子生物学分子生物学
背景情况:
- 异形性肺纤维化 (IPF) 是一种致命的肺病,由纤维细胞激活和原沉积驱动.
- 在IPF中纤维细胞激活与代谢重编程有关,包括增强的甘氨酸合成.
- 通过TGF-β,mTOR和ATF4精确调节纤维细胞代谢仍然不完全理解.
研究的目的:
- 研究mTOR和ATF4在调节TGF-β刺激的人类肺纤维细胞中的基因表达和代谢途径中的作用.
- 确定与IPF相关的纤维细胞代谢重编程中涉及的新型ATF4和mTOR依赖途径.
主要方法:
- 用TGF-β治疗的人类肺纤维细胞的RNA测序,以评估ATF4和mTOR调节的基因表达变化.
- 对细胞代谢物水平的分析,以确认ATF4和mTOR对代谢途径的影响.
- 来自IPF患者肺部的公开可用的单细胞RNA测序数据集的生物信息分析.
主要成果:
- ATF4主要调节涉及氨基酸稳态和氨基酸-tRNA合成酶的基因.
- mTOR抑制降低了ATF4向基因表达,也降低了糖分酶和线粒体电子运输链子单元的下调.
- ATF4和mTOR都影响着不同的代谢途径,包括氨基酸,糖解和TCA循环,它们的点在IPF纤维细胞中受到上调.
结论:
- 在TGF-β激活过程中,ATF4和mTOR是肺纤维细胞中代谢重编程的关键调节者.
- 这些发现阐明了新的ATF4-和mTOR-依赖的代谢途径,有助于IPF中的纤维细胞激活.
- 针对这些已识别的ATF4和mTOR通路,为抑制IPF纤维化过程提供了潜在的治疗策略.
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