治疗抗体显示成年肺的转化控制
Daniel Lafkas1, Amy Shelton1, Cecilia Chiu2
1Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Nature
|November 19, 2015
概括
痕信号调节了呼吸道细胞的命运. 在成年人呼吸道中,阻断带细胞转化为毛细胞,揭示出意想不到的可塑性和潜在的治疗应用.
科学领域:
- 细胞生物学
- 发育生物学
- 呼吸系统医学
背景情况:
- 传统上,涉及Jagged连接体 (JAG1,JAG2) 的Notch路径与分裂祖细胞的二进制细胞命运决定有关.
- 活跃的Notch信号在长期存在的成年人呼吸道上皮细胞中的作用在很大程度上尚未被探索.
- 呼吸道粘膜清除依赖于来自共同祖先的分泌细胞 (棒,杯) 和状细胞.
研究的目的:
- 在恒温条件下调查Jagged-Notch信号在成年上皮细胞可塑性的作用.
- 确定Jagged信号封锁是否可以诱导成年呼吸道细胞的细胞命运转化.
- 在呼吸道疾病中探索格抗性的治疗潜力.
主要方法:
- 对Jagged-1和Jagged-2体产生选择性抗体对手.
- 确定Jagged抗体复合物的晶体结构以解释选择性.
- 在成年哺乳动物中急性阻断Jagged信号.
- 分析呼吸道上皮层中的细胞命运变化,细胞死亡和细胞分裂.
- 在临床前喘模型中评估杯状细胞转化.
主要成果:
- 导致成年人平静的呼吸道快速丧失球状细胞和增加毛细胞.
- 细胞命运分析证实了直接的俱乐部细胞转化为毛细胞,没有增殖或增加细胞死亡.
- 在临床前喘模型中扭转了缩抑制的杯状细胞代谢.
- 结构分析阐明了对Jagged对抗体选择性的机制.
结论:
- 在成年人呼吸道上皮层中,Jagged-Notch信号积极维持细胞命运的稳定性,抑制细胞对细胞的转化.
- 急性格抗性诱导球状细胞直接转化为毛细胞,显现出显著的上皮质可塑性.
- 针对曲信号提供了以杯状细胞转化为特征的呼吸道疾病的潜在治疗策略.
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