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Linking the unfolded protein response to oxygen sensing - A phosphoproteomic approach to identify novel substrates of the ER kinase PERK

将未折叠蛋白响应与氧传感联系起来 - 一种识别 ER 激酶 PERK 新型底物的磷酸蛋白质组学方法

基本信息

批准号：
2599449
负责人：
金额：
--
依托单位：
University of Liverpool
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2599449
关键词：
Linking unfolded protein response oxygen

项目摘要

The unfolded protein response (UPR) is a process by which cells clear accumulations of misfolded and damaged proteins. Such accumulations are associated with a number of age-related diseases such as cancers and neurodegenerative disease. PERK, a kinase residing in the endoplasmic reticulum, has an essential role in the UPR. Activation of PERK halts global protein synthesis via the phosphorylation of the translation initiation factor, eIF2a. As with misfolded protein accumulation, aberrant PERK signalling is associated with a variety of diseases. Also implicated in several human diseases is the cellular response to low oxygen. Recent work in the Kenneth lab has shown a role for PERK in the regulation of the hypoxia-inducible factor (HIF)-dependent hypoxia response, however, the pathway underlying this regulatory link remains unclear. Using an unbiased phosphoproteomic screen and biochemical assays, we will first identify novel direct substrates of PERK. CRISPR experiments will then allow us to characterise the possible roles of these substrates in the regulation of the HIF-dependent response. Through this work we aim to further the understanding of the relationship between the UPR and hypoxia response, which may lead to targeted therapeutic strategies against pathologies related to misfolded protein accumulation.

未折叠蛋白反应（UPR）是细胞清除错误折叠和受损蛋白质积累的过程。这种积累与许多与年龄有关的疾病有关，如癌症和神经退行性疾病。PERK是一种存在于内质网中的激酶，在UPR中具有重要作用。PERK的激活通过翻译起始因子eIF2a的磷酸化来停止整体蛋白质合成。与错误折叠的蛋白质积累一样，异常PERK信号传导与多种疾病相关。与几种人类疾病有关的还有细胞对低氧的反应。Kenneth实验室最近的工作表明PERK在调节缺氧诱导因子（HIF）依赖性缺氧反应中发挥作用，然而，这种调节联系的潜在途径仍不清楚。使用一个公正的磷酸化蛋白质组学筛选和生化测定，我们将首先确定新的PERK直接底物。然后，CRISPR实验将使我们能够确定这些底物在调节HIF依赖性反应中的可能作用。通过这项工作，我们的目标是进一步了解UPR和缺氧反应之间的关系，这可能会导致针对与错误折叠蛋白质积累相关的病理的靶向治疗策略。