La function and the unfolded protein response

La 功能和未折叠蛋白反应

• 批准号: 371476-2009
• 负责人: Bayfield, Mark
• 金额: $ 2.91万
• 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: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=528229
• 关键词: La; function; 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. A major goal of my research program is to identify the mechanisms underlying the activation and regulation of an evolutionarily conserved stress adaptation known as the unfolded protein response (UPR) in the genetically and biochemically tractable model organism, Schizosaccharomyces pombe (fission yeast). The UPR is found in all higher organisms and is used to overcome a number of environmental challenges. Furthermore, the ability activate an effective UPR has been implicated in disease states. For several metabolic processes, fission yeast has been characterized as the most representative microbe in terms of evolutionary conservation with higher organisms, but its UPR remains to be described. One direction of my research program is to address this knowledge gap and provide significant insight into the regulation of the UPR in S. pombe and the nature of its evolutionary conservation and divergence. A separate but related element of my research program involves the La protein. This conserved cellular factor is critical to the normal maturation of various nucleic acid species (tRNAs) in the cell and also controls the expression of certain gene products at the RNA level. Importantly, it is thought to regulate the UPR through as yet unknown mechanisms. As my previous work has shown extensive conservation of La function between fission yeast and higher organisms, including humans, my research program will focus on delineating the function of this protein in the UPR of S. pombe and in the regulation of other RNAs more generally. The results of the proposed work will be used to develop comprehensive models for genetic regulation in stress responses. The elucidation of mechanisms of stress adaptation in S. pombe will be useful in extrapolating related pathways in higher organisms, and may provide insight into the characterization of microbial growth conditions and 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。微生物对压力作出反应的分子参与者和途径通常在高等生物中进化上是保守的。我的研究计划的一个主要目标是确定激活和调节进化上保守的应激适应的机制，称为未折叠蛋白反应（UPR）在遗传和生物化学上易于处理的模式生物，裂殖酵母（裂殖酵母）。普遍定期审议存在于所有高等生物中，用于克服许多环境挑战。 此外，激活有效UPR的能力与疾病状态有关。对于几个代谢过程，裂变酵母已被定性为最具代表性的微生物在进化上的保守性与高等生物，但其UPR仍有待描述。我的研究计划的一个方向是解决这一知识差距，并提供了重要的洞察到普遍定期审议的监管在S。粟酒裂殖酵母及其进化保守性和分化的性质。我的研究计划中一个独立但相关的元素涉及La蛋白。这种保守的细胞因子对细胞中各种核酸种类（tRNA）的正常成熟至关重要，并且还在RNA水平上控制某些基因产物的表达。重要的是，它被认为是通过迄今未知的机制来管理普遍定期审议。由于我以前的工作已经显示了La功能在裂变酵母和高等生物（包括人类）之间的广泛保守性，我的研究计划将集中在描绘这种蛋白质在S.粟球蛋白以及更普遍地调节其他RNA。拟议工作的结果将用于开发全面的模型，在压力反应的遗传调控。阐明了S.粟酒裂殖酵母将有助于推断高等生物中的相关途径，并可能为微生物生长条件的表征和新抗微生物剂的设计提供见解。