Mechanisms of Regulation of the Unfolded Protein Response

未折叠蛋白反应的调节机制

• 批准号: RGPIN-2014-05567
• 负责人: Bayfield, Mark
• 金额: $ 2.55万
• 依托单位: York University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=567249
• 关键词: Mechanisms; Regulation; Unfolded; Protein; Response

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.

适应环境压力的能力对于所有生命形式的生存至关重要。微生物应对应激的分子参与者和途径在高等生物中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初步发现通常是在研究细菌和酵母等简单生物体时首先发现的。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压力的机制，通常称为未折叠蛋白质反应（UPR）。这种进化上保守的应激适应存在于所有高等生物中，并用于克服许多环境挑战。无法激活有效的 UPR 也与疾病状态有关。为了研究细胞如何有效进行 UPR 的常见策略，我们使用了模型生物裂殖酵母（裂殖酵母）。我们使用裂殖酵母，因为可用于这种生物的科学工具非常丰富；其遗传和生化操作都有完善且可用的方法。此外，对于一些代谢过程，裂殖酵母被认为是与包括人类在内的高等生物的进化保守性方面最具代表性的微生物。我们和其他小组的初步数据表明，裂殖酵母以一种与其他简单生物体中已阐明的显着不同的方式启动有效的 UPR，因此，对该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其他细胞（包括人类细胞）如何适应压力。因此，我的研究项目致力于解决对粟酒裂殖酵母中未折叠蛋白质反应知识的缺乏，并研究其进化保守性和分化的本质。阐明粟酒裂殖酵母的应激适应机制将有助于推断高等生物中的相关途径，将提供对微生物生长条件特征的深入了解，并可能有助于设计新的抗微生物药物。