顽固群细胞是指对抗生素敏感的单克隆细菌群体中，在大剂量、长时间抗生素作用下仍然能够存活的一小部分不生长的休眠细胞。顽固群细胞是造成感染复发和细菌耐药性变异的源头。目前认为顽固群形成的直接机制是高度冗余的毒素-抗毒素模块的主动表达所致，而且是在细胞群体中随机产生的，无需诱导。然而，细菌在压力条件下的严紧反应/SOS反应能够诱导提高顽固群在群体中的比例。根据前期结果本研究提出顽固群细胞是细菌在压力条件下动态产生的各种表型亚群中的一群，存在共同的调控通路。本课题首先通过微流控细胞芯片观察不同压力条件下细菌群体的生长等表型变化和顽固群细胞形成的动态过程；然后应用转录组测序和流式分选技术，对不同压力条件下顽固群细胞及其祖先细胞亚群的转录组动态变化进行比较，重点考查与严紧反应/SOS反应、生长调控相关基因，并通过基因敲除和补充表达验证其功能，确定顽固群细胞形成的关键分子机制和调节基因。

Persister is a dynamic subset of clonal bacterial population that often survives after antibiotic treatment even when the drug is at high-dosages. Persister is slow-growing, has a low metabolic activity, and is often regarded as the source of infection relapse and genetic resistance. Persister is a result of actively expressed toxin-antitoxin (TA) modules among different isolates of a bacterium. Lines of evidence confirm persister adaptation under environmental stresses and its dynamics as subpopulations with variable proportions within the population especially under stringent and/or SOS response. We propose that persister, taking a population strategy for survival, represents a subpopulation that is gradually generated from the population in response to stresses and coordinates with other subpopulations. Here, we plan to investigate this bacterial population strategy and to understand how persister cells regulate their genes under variable stresses, using a microfluidic device and micro-cultural methodology. We will use transcriptomic tools to explore molecular details of the population dynamics under stresses and stringent/SOS response and confirm the results with gene knockout and complementary expression.