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）是一种具有多方面功能的细胞器，是蛋白质合成、修饰和细胞器间通讯的中心。它与线粒体、溶酶体和质膜广泛合作，促进重要代谢物、脂质和蛋白质的转运。最近的研究，包括我们自己的研究，揭示了一个称为ER-吞噬的过程，其中ER通过自噬进行靶向降解，以响应各种应激源，如氨基酸剥夺，蛋白质错误折叠和细胞分化（1，2）。我们最近的数据表明，ER-吞噬也作为一个备份途径的蛋白酶体介导的ER相关的降解（ERAD）途径在ER应激和ERAD被抑制时，其活性被放大。然而，ERAD和ER-吞噬之间的潜在机制和串扰仍然不清楚，并形成了这个博士项目的基础。这项工作的这一潜在结果特别令人兴奋，并可能暗示利用ER-吞噬激活作为与ERAD缺陷相关的疾病的替代策略，这些疾病包括肥胖和代谢紊乱，神经退行性疾病和多聚谷氨酰胺疾病。 在这个博士项目中，我们的目标是识别和表征参与刺激诱导的ER-吞噬的新的关键参与者，最终目标是阐明ER-吞噬的生理作用和病理后果。建立在我们建立的检测和初步数据，我们的目标是解决以下问题：什么是基本组成部分精心策划ER应激诱导ER-吞噬？使用遗传学，生物化学和质谱，我们将深入研究分子景观，以揭示负责启动和执行ER-吞噬的关键参与者。这些关键角色是如何在压力下被调节和激活的？这些关键角色是如何在压力下被调节和激活的？我们将使用蛋白质组学和基因表达分析来了解翻译后修饰和调控网络，管理ER-吞噬失败的ER-吞噬的整体含义是什么？通过研究受损的ER-吞噬的影响，我们将更深入地了解异常ER-吞噬过程导致的病理结果和潜在的疾病关联。