La function and 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。我的研究计划的一个主要目标是确定在遗传和生物化学上容易处理的模式生物裂殖酵母(裂殖酵母)中，一种被称为未折叠蛋白反应(UPR)的进化保守的应激适应的激活和调节机制。UPR在所有高等生物体中都存在，并用于克服一些环境挑战。此外，激活有效的UPR的能力与疾病状态有关。在几个代谢过程中，裂解酵母被认为是最具代表性的微生物，与高等生物进化保守，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，并对S.pombe的UPR的调节及其进化保守和分化的性质提供重要的见解。我的研究计划中另一个独立但相关的元素涉及La蛋白质。这种保守的细胞因子对细胞中各种核酸物种(TRNAs)的正常成熟至关重要，也在RNA水平上控制某些基因产物的表达。重要的是，它被认为通过尚不为人所知的机制来管理普遍定期审议。由于我之前的工作已经显示了La在分裂酵母和包括人类在内的高等生物之间的广泛保守，我的研究计划将集中在描述这种蛋白在S.pombe的UPR中的功能以及在更广泛的其他RNA的调节中的功能。这项拟议工作的结果将被用来开发应激反应中遗传调控的综合模型。阐明S.pombe的逆境适应机制将有助于推断高等生物体中的相关途径，并可能为微生物生长条件的表征和新型抗微生物药物的设计提供洞察。

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.