Consequences of the metazoan unfolded protein response

描述（由申请人提供）：未折叠蛋白反应（UPR）最初被认为是与内质网（ER）中未折叠蛋白积累相关的应激反应，已被证明在后生动物的发育和专门分泌的细胞分化中发挥关键作用。UPR在酵母中得到了最好的表征，其中一个简单的线性途径激活了参与分泌蛋白折叠和降解的基因的转录。然而，在内塔动物中发现的其他成分表明，高等真核生物中的UPR更为复杂，涉及几个平行途径，并影响转录和翻译。然而，单个组件如何执行其扩展功能仍然知之甚少。通过本文所述的研究，我们希望通过确定后生动物中UPR的转录范围，破译所涉及的平行响应元件的差异效应，并从功能上分析该响应的靶标，重点研究UPR与分泌蛋白的er相关降解（ERAD）之间的关系，从而深入了解这一过程。我们还计划测试关于反应的不同元素的时间协调和细胞区分最终错误折叠与过度丰富蛋白质的能力的特定假设。

DESCRIPTION (provided by applicant): The unfolded protein response (UPR), originally identified as a stress response associated with the accumulation of unfolded proteins in the endoplasmic reticulum (ER), has been shown to play a key role in development of metazoans and in differentiation of cells specializing in secretion. The UPR is best characterized in yeast, where a simple linear pathway activates the transcription of genes involved in the folding and degradation of secreted proteins. The discovery of additional components in rnetazoans, however, has shown that the UPR in higher eukaryotes is more complex, involving several parallel pathways and affecting both transcription and translation. How the individual components carry out their expanded function, however, remains poorly understood. Through the research described here, we hope to gain insight into this process by determining the transcriptional scope of the UPR in metazoans, deciphering the differential effects of the parallel response elements involved, and functionally analyzing the targets of the response, focusing on the relationship between the UPR and ER-associated degradation (ERAD) of secreted proteins that fail to fold or oligomerize properly. We also plan to test specific hypotheses regarding the coordination of the timing of different elements of the response and the ability of the cell to distinguish between terminally misfolded vs. overly abundant proteins.