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: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=611712
• 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所有生命形式的生存至关重要。微生物对应激反应的分子机制和途径在高等生物中通常是进化保守的。因此，对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其蛋白质被折叠的压力的机制，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。无法激活有效的普遍定期审议也与疾病状态有关。为了研究细胞如何安装一个有效的UPR的共同策略，我们正在使用模式生物裂糖酵母pombe（裂变酵母）。我们使用裂变酵母是因为有丰富的科学工具可用来研究这种生物；对于其基因和生化操作都有完善和可用的方法。此外，在一些代谢过程中，裂变酵母菌被认为是与包括人类在内的高等生物进化守恒方面最具代表性的微生物。我们和其他研究小组的初步数据表明，裂变酵母以一种与其他简单生物截然不同的方式装载有效的UPR，因此，对这种生命系统中的这种应激反应的研究可能为我们提供对其他细胞（包括人类细胞）如何适应压力的独特见解。因此，我的研究项目致力于解决S.pombe中未折叠蛋白反应的知识缺乏问题，并研究其进化保护和分化的本质。阐明S. pombe的应激适应机制将有助于推断高等生物的相关途径，为微生物生长条件的表征提供见解，并可能有助于设计新的抗微生物药物。