Role of Luman/CREB3 and Zhangfei/CREBZF in cellular stress responses and neuronal regeneration

细胞受到压力的原因有很多：缺氧或营养物质缺乏、邻近活跃生长细胞的副产品、感染病原体的副产品或结构成分、免疫系统的产物、制造蛋白质的过度需求以及对细胞或周围组织的损害。细胞通过激活特定的反应来应对这些压力源。虽然细胞应激反应对宿主有益，但它们也可能有害。例如，疱疹病毒已经进化到在宿主体内潜伏，直到宿主受到压力。然后，它们利用这些反应中的一些来感知压力并重新激活。此外，应激反应还使癌细胞能够在缺氧、辐射和抗癌药物中存活并转移。在之前的NSERC-Discovery资助项目中，我们发现了两种独特的细胞蛋白，我们将其命名为Luman和Zhangfei。这些蛋白在神经元中表达，可能被单纯疱疹病毒用来决定是否复制、潜伏或重新激活。鲁曼和张飞的作用是交叉的——鲁曼刺激病毒和宿主基因的表达，而张飞抑制它。自发现以来，我们的实验室和其他研究人员已经确定，这两种蛋白质参与了多种重要的生物过程，包括调节应激反应、调节胰岛素的合成、允许树突状细胞（启动身体对病原体的反应的细胞）成熟和启动受损感觉神经元的修复。虽然我们很高兴看到我们最初的发现引起了这么多的兴趣，但我们仍然不知道鲁曼和张飞是如何发挥它们的许多功能的。我们的建议就是试图确定这一点。关于Luman，我们将重点研究它在损伤神经元恢复中的作用。我们将结合使用活细胞显微镜和基因表达、蛋白激酶和细胞内信号通路的测量来确定Luman是如何从损伤部位运输到细胞体的，以及它到达那里时的作用。我们还将研究张飞如何能够抑制介导应激反应和癌细胞生长的基因激活因子的活性。

Cells can be stressed for many reasons: lack of oxygen or nutrients, by-products of neighbouring actively growing cells, by products or structural components of infecting pathogens, products of the immune system, excessive demands to make protein and damage to the cell or surrounding tissue. Cells react by activating specialized responses that allow them to cope with these stressors. While cellular stress responses are meant to benefit the host, they can be detrimental as well. For instance, herpesviruses have evolved to remain latent in their hosts until their host is stressed. They then exploit some of these responses to sense stress and reactivate. In addition, stress responses also allow cancer cells to survive hypoxia, radiation and anti-cancer drugs and to metastasize. In a previous NSERC-Discovery grant funded proposal we discovered two unique cellular proteins which we named Luman and Zhangfei. These proteins are expressed in neurons and may be used by herpes simplex virus to decide whether to replicate, become latent or reactivate. Luman and Zhangfei act at cross-purposes - Luman stimulates viral and host gene expression while Zhangfei suppresses it. Since their discovery, our laboratory and others have determined that the two proteins are involved in a wide variety of important biological processes including modulating stress responses, regulating the synthesis of insulin, allowing dendritic cells (cells that initiate the body's response to pathogens) to mature and initiating the repair of injured sensory neurons. While it is gratifying to see that our initial discovery has generated so much interest, we still do not know how Luman and Zhangfei perform their many functions. Our proposal is an attempt to determine this. Regarding Luman, we will focus on its role in the recovery of the injured neuron. We will use a combination of live-cell microscopy and measurement of gene expression, protein kinases and intracellular signalling pathways to determine how Luman is transported from the site of injury to the cell body and what it does when it gets there. We will also study how Zhangfei is able to suppress the activity of gene activators that mediate stress responses and cancer cell growth.