Mechanisms of Regulation of the Unfolded Protein Response

适应环境压力的能力对所有生命形式的生存至关重要。在高等生物体中，微生物对压力作出反应的分子参与者和途径通常在进化上是保守的。因此，关于活细胞如何适应压力环境的最初发现是在研究细菌和酵母等简单生物时首次发现的，这是很常见的。我的研究计划的一个主要目标是确定细胞适应蛋白质展开的压力的机制，通常被称为未折叠蛋白质反应(UPR)。这种进化上保守的应激适应在所有高等生物中都存在，并被用来克服许多环境挑战。无法激活有效的UPR也与疾病状态有关。为了研究细胞如何安装有效的UPR的常见策略，我们使用了模式生物裂殖酵母(裂殖酵母)。我们使用裂解酵母是因为有丰富的科学工具可以用来研究这种有机体；对于它的遗传和生化操作，已经有了成熟和可用的方法。此外，在几个代谢过程中，裂解酵母被认为是与包括人类在内的高等生物进化保护方面最具代表性的微生物。来自我们和其他团队的初步数据表明，分裂酵母以一种与其他简单生物体中所阐明的显著不同的方式安装有效的UPR，因此，对这个生命系统中的这种应激反应的研究可能为我们提供独特的见解，了解包括人类细胞在内的其他细胞如何适应应激。因此，我的研究计划致力于解决对S.pombe中未折叠蛋白反应的了解不足，并检查其进化保守和分歧的本质。阐明S.pombe的胁迫适应机制将有助于推断高等生物体中的相关途径，将有助于深入了解微生物生长条件的特征，并可能有助于设计新的抗微生物药物。

The capacity to adapt to environmental stresses is critical for the viability of all life forms. The molecular players and pathways by which microbes respond to stress are often evolutionarily conserved in higher organisms. It is therefore common that the initial discoveries for how living cells adapt to stressful situations are first made while studying simple organisms like bacteria and yeast. A major goal of my research program is to identify the mechanisms by which cells adapt to the stress of having their proteins become unfolded, commonly known as the unfolded protein response (UPR). This evolutionarily conserved stress adaptation is found in all higher organisms and is used to overcome a number of environmental challenges. The inability to activate an effective UPR has also been implicated in disease states. To study common strategies of how cells mount an effective UPR, we are using the model organism Schizosaccharomyces pombe (fission yeast). We use fission yeast because of the richness of scientific tools available for this organism; there are well-established and available methods for both its genetic and biochemical manipulation. Furthermore, for several metabolic processes, fission yeast has been characterized as the most representative microbe in terms of evolutionary conservation with higher organisms, including humans. Preliminary data from both our and other groups indicate that fission yeast mount an effective UPR in a significantly different way than has been elucidated in other simple organisms, and as such the study of this stress response in this living system may provide us with unique insight into how other cells, including human cells, adapt to stress. Thus, my research program is dedicated to addressing the lack of knowledge about the unfolded protein response in S.pombe and to examine the nature of its evolutionary conservation and divergence. The elucidation of mechanisms of stress adaptation in S. pombe will be useful in extrapolating related pathways in higher organisms, will provide insight into the characterization of microbial growth conditions, and may assist in the design of new anti-microbials.