斑马鱼pmm2it768突变体 Nrf2信号通路的活性化机制研究

With response to the irritation of varied environmental factors, Nrf2 system can active antioxidant protein and the phase II detoxification enzyme to enhance the metabolizing of hazardous material and diminish the damnification by the environmental toxic. Recent studies indicated that the Nrf2 system can not only be activated by exogenous environmental stimuli, but also can be activated by endogenous active substances. In order to study the mechanism of Nrf2 system activity, especially the regulation mechanism of endogenous cell pressure on Nrf2 signaling pathway, we selected pmm2it768, the activated mutant of Nrf2, by ENU mutation screening experiments, which was enhanced by endogenous cellular stress and abnormal liver development. Here, utilizing pmm2it768 mutant，we will study the molecular mechanism of Nrf2 signaling pathway activated by Endogenous cellular stress; explore the regulation mechanism of cell stress on individual development. Vertebrate animals maintain reproductive development by adapting themselves to the varied environments. Nrf2 system is one of the important protective systems under the stimulation of cell environment, which is closed to the tissue development and is connect to the many kinds of diseases. In this study, from the perspective of intracellular environment, we hope to understand deeply the activation mechanism of Nrf2 signaling pathway, which is significant to the health protection and disease treatment under the environmental stimuli.

Nrf2信号通路能对多种环境刺激做出应答，激活抗氧化蛋白和第二相解毒酶群，促进有害物质代谢解毒。近年的研究发现Nrf2系统不仅可以被外源性环境刺激激活，还可以被内源性细胞活性物质激活。为了研究Nrf2系统多样的活性化机制，特别是内源性细胞压力对Nrf2信号通路的调控机制，我们通过ENU变异筛选实验，选取了Nrf2信号通路活性化突变体pmm2it768。该突变体的表型为内源性细胞压力增强，及肝脏发育异常。本课题利用该突变体，从正方向遗传学的角度解析内源性细胞压力激活Nrf2信号通路的分子机制，探究细胞压力对个体发育的调控机制。脊椎类动物通过适应各种环境维持生殖发育的正常进行，Nrf2系统是细胞环境刺激下重要的防护系统之一，与组织发育以及多种疾病紧密相关。本课题从细胞内环境角度出发，以期全面理解Nrf2信号通路的活性化机制，为环境刺激下机体的健康防护与疾病治疗提供科学的基础和理论依据。

Nrf2系统通过诱导多种细胞保护基因，在生物体防御亲电物质和氧化应激方面发挥重要作用。为了了解Nrf2系统的多方面功能和调控，我们建立了斑马鱼分子研究模型，分离了一个在恒常状态下Nrf2目标基因gstp1高表达的斑马鱼突变体pmm2it768。通过定位克隆，确定了pmm2it768的突变基因为斑马鱼的Pmm2。Pmm2it768表现出Nrf2的高度活性化，以及肝脏的损伤。通过进一步的解析发现Nrf2的活性化来源于内源性的细胞压力，确定为内质网应激。内质网应激通过PERK途径调控Nrf2的活性化，并引起肝脏损伤。这一结论还通过了其他三种分子模型进行了验证，即TM、TG内质网应激诱导剂诱发的肝损伤模型、高脂饮食肝损伤模型、TAA+ Fe2+肝损伤模型。研究共得到以下三个结论：内质网应激可调控内Nrf2以及下游基因的表达并引起肝脏损伤；肝脏损伤（包括脂肪肝和肝纤维化）与内质网应激密切相关；Nrf2的表达平衡是控制肝脏病变的发生关键因素。本项目研究证明内质网应激与Nrf2的活性化以及肝脏损伤密切相关。为肝病治疗开辟了一个新途径。

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