前药
细胞
效应器
硝基还原酶
转基因
功能(生物学)
细胞生物学
酶
化学
生物
计算生物学
生物化学
基因
作者
Abigail V. Sharrock,Timothy S. Mulligan,Kelsi R Hall,Elizabeth Williams,David T. White,Liyun Zhang,Kevin Emmerich,Frazer Matthews,Saumya Nimmagadda,Selena Washington,Katherine Le,Danielle Meir-Levi,Olivia L. Cox,Mohit Saxena,Anne L. Calof,Martha E. Lopez-Burks,Arthur D. Lander,Ding Ding,Hongkai Ji,David F. Ackerley,Jeff S. Mumm
出处
期刊:Nature Methods
[Springer Nature]
日期:2022-02-01
卷期号:19 (2): 205-215
被引量:31
标识
DOI:10.1038/s41592-021-01364-4
摘要
Transgenic expression of bacterial nitroreductase (NTR) enzymes sensitizes eukaryotic cells to prodrugs such as metronidazole (MTZ), enabling selective cell-ablation paradigms that have expanded studies of cell function and regeneration in vertebrates. However, first-generation NTRs required confoundingly toxic prodrug treatments to achieve effective cell ablation, and some cell types have proven resistant. Here we used rational engineering and cross-species screening to develop an NTR variant, NTR 2.0, which exhibits ~100-fold improvement in MTZ-mediated cell-specific ablation efficacy, eliminating the need for near-toxic prodrug treatment regimens. NTR 2.0 therefore enables sustained cell-loss paradigms and ablation of previously resistant cell types. These properties permit enhanced interrogations of cell function, extended challenges to the regenerative capacities of discrete stem cell niches, and novel modeling of chronic degenerative diseases. Accordingly, we have created a series of bipartite transgenic reporter/effector resources to facilitate dissemination of NTR 2.0 to the research community.
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