Project Title Unraveling the Mysteries of ER-phagy: Exploring the Intricate Pathways of ER Stress-Induced ER-phagy

项目名称 揭开内质网自噬之谜：探索内质网应激诱导内质网自噬的复杂途径

• 批准号: 2876792
• 金额: --
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2876792
• 关键词: Project; Title; Unraveling; Mysteries; ER

The Endoplasmic Reticulum (ER) is a remarkable organelle with multifaceted functions, serving as the epicenter of protein synthesis, modification, and inter-organelle communication. It collaborates extensively with mitochondria, lysosomes, and the plasma membrane, facilitating the transport of vital metabolites, lipids, and proteins. Recent studies, including our own research, have shed light on a process called ER-phagy, wherein the ER undergoes targeted degradation through autophagy in response to various stressors such as amino acid deprivation, protein misfolding, and cellular differentiation(1,2). Our recent data suggest that ER-phagy also acts as a backup pathway to the proteasome-mediated ER-associated degradation (ERAD) pathway during ER stress and its activity is amplified when ERAD is inhibited. However, the underlying mechanism and crosstalk between ERAD and ER-phagy remain unclear and forms the basis of this PhD project. This potential outcome of this work is particularly exciting and could hint towards leveraging ER-phagy activation as an alternative strategy in diseases related to ERAD defects ranging from obesity and metabolic disorders, to neurodegenerative diseases and polyglutamine diseases. In this PhD project, we aim to identify and characterize novel key players involved in stimulus-induced ER-phagy, with the ultimate goal of shedding light on both the physiological roles and pathological consequences of ER-phagy. Building upon our established assays and preliminary data, we aim to address the following questions: What are the fundamental components orchestrating ER stress-induced ER-phagy? Using genetics, biochemistry, and mass spectrometry, we will delve into the molecular landscape to uncover the critical players responsible for initiating and executing ER-phagy. How are these key players regulated and activated in response to stress? How are these key players regulated and activated in response to stress? We will use proteomics and gene expression analysis to understand the post-translational modifications and regulatory networks that govern ER-phagy What is the overall implication of failed ER-phagy? By investigating the repercussions of impaired ER-phagy, we will gain a deeper understanding of the pathological outcomes and potential disease associations resulting from aberrant ER-phagy processes.

内质网（ER）是具有多方面功能的显着细胞器，是蛋白质合成，修饰和轨道间通信的中心。它与线粒体，溶酶体和质膜广泛合作，促进了重要的代谢物，脂质和蛋白质的运输。最近的研究，包括我们自己的研究，已经揭示了一个称为ER-Phagy的过程，其中ER通过自动噬菌体对各种压力源（例如氨基酸剥夺，蛋白质错误折叠和细胞分化）进行靶向降解（1,2）。我们最近的数据表明，ER-Phagy还充当蛋白酶体介导的ER相关降解（ERAD）途径的备份途径，当ER抑制ERAD时，其活性会放大。但是，Erad和Er-Phagy之间的基本机制和串扰尚不清楚，并构成了该博士学位项目的基础。这项工作的这一潜在结果特别令人兴奋，可以暗示利用ER-Phagy激活作为与埃拉德缺陷有关的替代策略，从肥胖和代谢性疾病到神经退行性疾病和多谷氨酰胺疾病。 在这个博士学位项目中，我们旨在识别和表征参与刺激引起的ER-PHAGY的新型主要参与者，其最终目标是阐明ER-PHAGY的生理角色和病理后果。在我们既定的分析和初步数据的基础上，我们旨在解决以下问题：策划ER压力引起的ER-Phagy的基本组件是什么？使用遗传学，生物化学和质谱法，我们将深入研究分子景观，以发现负责发起和执行ER-Phagy的关键参与者。这些主要参与者如何根据压力受到调节和激活？这些主要参与者如何根据压力受到调节和激活？我们将使用蛋白质组学和基因表达分析来了解控制ER-Phagy的翻译后修饰和调节网络，而ER-Phagy失败的总体含义是什么？通过研究ER-PHAGY受损的影响，我们将对异常的ER-Phagy过程产生的病理结局和潜在疾病关联有更深入的了解。