PRAK介导的氧化应激反应对Treg/Th17分化的调节在哮喘中的作用

PRAK belongs to MAPK family and it mainly responses to the oxidative stress as a p38 activation kinase. Our previous data showed that PRAK was fundamental to the activation，survival and maintenance of the mitochondria function of T cells. The funding we apply now plans to take the advantage of PRAK knockout mice, and try to figure out how PRAK regulate T cells in asthma, especially steroid resistant asthma. We will study whether PRAK could influence the stability of Foxp3, which is the essential transcription factor of Tregs and furthermore, whether PRAK could interfere on the signal of IL-6-Stat3-RORγt activated by the initiation of Th17 differentiation directly or indirectly. Finally, we will analysis if PRAK can alter the Th17/Treg ratio and the inflammatory effect of Th17 in asthma. The results from this research will help illustrate how the environment could affect the T cell differentiation and moreover how ROS could influence the metabolism of T cells, and will provide a far more precise guiding strategy for the severe asthma therapy.

PRAK是MAPK激活蛋白激酶亚家族之一，其主要作为p38的下游激酶在细胞对氧化应激的反应中起作用。申请人在前期研究中发现，PRAK对T细胞的活化、存活以及线粒体功能的维持起着不可或缺的作用。本项目将借助PRAK基因敲除小鼠，研究在哮喘疾病特别是激素不敏感的Th17依赖型重症哮喘中，PRAK介导的氧化应激信号的如何调动一系列线粒体相关或非线粒体相关机制来调控Treg细胞转录因子Foxp3的稳定性，并进一步分析PRAK是否能直接或间接地激活Th17细胞分化必需的IL-6-Stat3-RORγt的信号，最终确定PRAK对Th17/Treg细胞分化平衡和Th17的炎症效应的影响。研究结果有利于进一步揭示环境压力的改变对T细胞分化的影响，阐明活性氧ROS对T细胞的代谢重塑过程，为临床重症哮喘的治疗提供更精确的指导策略。

为研究慢性炎症和肿瘤微环境中存在的氧化应激压力如何调节T细胞功能的问题，本项目以PRAK基因敲除小鼠为对象，研究在脊髓炎和结直肠癌疾病中，PRAK介导的氧化应激信号如何调动氧化磷酸化和糖酵解相关机制来调控Treg细胞与Th17细胞的分化。通过对胞内ROS、抗氧化应激分子Nrf2的稳定性、T细胞糖酵解能力、Th17细胞分化关键信号分子Stat3的活性状态的研究，本项目论证了PRAK缺陷会导致Th17细胞发生氧化应激，揭示了PRAK调控蛋白NRF2稳定性的新机制，发现了PRAK可通过Nrf2分子清除胞内ROS和抑制细胞糖酵解以及破坏PKM2介导的STAT3磷酸化从而抑制Th17细胞分化必需的IL-6-Stat3-RORγt的信号，最终确定PRAK对Th17/Treg细胞分化平衡和Th17的炎症和促肿瘤效应的影响。研究结果有利于进一步完善环境代谢压力的改变对T细胞分化的影响，阐明活性氧ROS对T细胞的代谢重塑过程，为Treg/Th17平衡失调的肿瘤和部分炎症治疗提供更精确临床策略提供了理论依据。