Signaling Cross-talk Between Endoplasmic Reticulum And Oxidative Stresses
内质网和氧化应激之间的信号串扰
基本信息
- 批准号:RGPIN-2017-06414
- 负责人:
- 金额:$ 4.95万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2022
- 资助国家:加拿大
- 起止时间:2022-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Organisms must respond to a broad array of stresses which they may encounter during their lifespan. Stresses often occur, not as a single occurrence, but as multiple stresses which impinge upon the organism simultaneously. Stresses such as toxin stress, oxidative stress, low oxygen (hypoxic) stress and endoplasmic reticulum (ER) stress often occur concurrently. “Crosstalk” between multiple stresses often involves common protein factors which respond to a variety of extra- and intra-cellular signals. My research program focuses on one such protein that responds to multiple signalling processes and examines how these signals interact, either synergistically or antagonistically, to affect its function. Nuclear factor erythroid 2 like 1 (NFE2L1 or Nrf1) is a "cap'n'collar" basic leucine zipper transcription factor that heterodimerizes with small Maf proteins and bind to a DNA element known as the Antioxidant Response Element/Electrophile Response Element, required to transactivate antioxidant enzyme, phase 1 and 2 detoxification enzyme and proteasome subunit gene expression. Nrf1 responds to oxidative stress and regulates pathways involved in lipid metabolism, amino acid metabolism, proteasomal degradation, the citric acid cycle, and the mitochondrial respiratory chain. An unanswered question is the possibility that Nrf1 may also respond to ER stress, but how this occurs and how environmental stresses (toxin stress, hypoxia, oxidative stress) work in tandem with ER stress to affect Nrf1 function remains to be investigated. We recently demonstrated that a) hypoxia affects the way that Nrf1 is proteolytically processed, b) various environmental toxins affect the translocation of Nrf1 to the nucleus and c) phosphorylation of key tyrosines on the protein affect its ubiquitination and anchoring to the ER. The aims outlined in this proposal set out to demonstrate that cross-talk occurs between multiple environmental stressors and ER stress on Nrf1 function in mammalian cells. Aim 1 will examine the factors responsible for the proteolytic processing of Nrf1 and how these are altered by environmental stresses. Aim 2 will focus on stress-dependent post-translational modifications of the Nrf1 protein that affect its glycosylation, proteolytic processing and release from the ER under different stress conditions. Aim 3 will investigate the cross-talk between environmental stresses with ER stress in activating Nrf1. My long-term goals are to illustrate the importance of Nrf1 in the response to a broad range of cellular stresses and how these stresses act to affect its a) post-translational modification, b) release from the ER and translocation to the nucleus, c) proteolytic processing as well as determining whether multiple extra- and intracellular signals act synergistically or antagonistically on Nrf1. Similar mechanisms may apply to a number of different stress-response proteins.
生物体必须对其一生中可能遇到的各种各样的压力作出反应。压力经常发生,不是作为一个单一的事件,而是作为多重压力同时冲击有机体。应激如毒素应激、氧化应激、低氧(缺氧)应激和内质网(ER)应激往往同时发生。多种应激之间的“串扰”通常涉及对各种细胞外和细胞内信号作出反应的共同蛋白质因子。我的研究项目集中在一个这样的蛋白质,响应多个信号过程,并检查如何这些信号相互作用,无论是协同或拮抗,影响其功能。核因子红细胞2样1 (NFE2L1或Nrf1)是一种“cap'n'collar”碱性亮氨酸拉链转录因子,与小Maf蛋白异二聚体结合,并结合被称为抗氧化反应元件/亲电反应元件的DNA元件,需要反激活抗氧化酶,第1期和第2期解毒酶和蛋白酶体亚基基因表达。Nrf1响应氧化应激并调节脂质代谢、氨基酸代谢、蛋白酶体降解、柠檬酸循环和线粒体呼吸链等途径。一个悬而未决的问题是Nrf1也可能对内质网应激作出反应,但这是如何发生的,以及环境应激(毒素应激、缺氧、氧化应激)如何与内质网应激协同作用影响Nrf1的功能仍有待研究。我们最近证明了a)缺氧影响Nrf1蛋白水解加工的方式,b)各种环境毒素影响Nrf1向细胞核的易位,c)蛋白质上关键酪氨酸的磷酸化影响其泛素化和锚定到内质网。本提案概述的目的是证明在哺乳动物细胞中,多种环境应激源和内质网应激对Nrf1功能之间发生串扰。目的1将检查负责Nrf1蛋白水解加工的因素以及这些因素如何被环境胁迫改变。Aim 2将关注Nrf1蛋白在不同应激条件下影响其糖基化、蛋白水解加工和从内质网释放的胁迫依赖性翻译后修饰。目的3将研究环境应激与内质网应激在激活Nrf1中的交互作用。我的长期目标是阐明Nrf1在广泛的细胞应激反应中的重要性,以及这些应激如何影响其a)翻译后修饰,b)从内质网释放并易位到细胞核,c)蛋白水解加工,以及确定多种细胞外和细胞内信号是否协同或拮抗Nrf1。类似的机制可能适用于许多不同的应激反应蛋白。
项目成果
期刊论文数量(0)
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{{ truncateString('Willmore, William', 18)}}的其他基金
Hypoxic incubators to conduct studies in low oxygen environments
低氧培养箱可在低氧环境下进行研究
- 批准号:
RTI-2023-00502 - 财政年份:2022
- 资助金额:
$ 4.95万 - 项目类别:
Research Tools and Instruments
Signaling Cross-talk Between Endoplasmic Reticulum And Oxidative Stresses
内质网和氧化应激之间的信号串扰
- 批准号:
RGPIN-2017-06414 - 财政年份:2021
- 资助金额:
$ 4.95万 - 项目类别:
Discovery Grants Program - Individual
Signaling Cross-talk Between Endoplasmic Reticulum And Oxidative Stresses
内质网和氧化应激之间的信号串扰
- 批准号:
RGPIN-2017-06414 - 财政年份:2020
- 资助金额:
$ 4.95万 - 项目类别:
Discovery Grants Program - Individual
Signaling Cross-talk Between Endoplasmic Reticulum And Oxidative Stresses
内质网和氧化应激之间的信号串扰
- 批准号:
RGPIN-2017-06414 - 财政年份:2019
- 资助金额:
$ 4.95万 - 项目类别:
Discovery Grants Program - Individual
Hypoxic workstation to conduct studies in low oxygen environments
低氧工作站可在低氧环境下进行研究
- 批准号:
RTI-2019-00935 - 财政年份:2018
- 资助金额:
$ 4.95万 - 项目类别:
Research Tools and Instruments
Signaling Cross-talk Between Endoplasmic Reticulum And Oxidative Stresses
内质网和氧化应激之间的信号串扰
- 批准号:
RGPIN-2017-06414 - 财政年份:2018
- 资助金额:
$ 4.95万 - 项目类别:
Discovery Grants Program - Individual
Signaling Cross-talk Between Endoplasmic Reticulum And Oxidative Stresses
内质网和氧化应激之间的信号串扰
- 批准号:
RGPIN-2017-06414 - 财政年份:2017
- 资助金额:
$ 4.95万 - 项目类别:
Discovery Grants Program - Individual
"Mitochondrial biogenesis and the decline of hypoxia, oxidative stress and toxin tolerance with age"
“线粒体生物发生以及缺氧、氧化应激和毒素耐受性随着年龄的增长而下降”
- 批准号:
250649-2012 - 财政年份:2016
- 资助金额:
$ 4.95万 - 项目类别:
Discovery Grants Program - Individual
"Mitochondrial biogenesis and the decline of hypoxia, oxidative stress and toxin tolerance with age"
“线粒体生物发生以及缺氧、氧化应激和毒素耐受性随着年龄的增长而下降”
- 批准号:
250649-2012 - 财政年份:2015
- 资助金额:
$ 4.95万 - 项目类别:
Discovery Grants Program - Individual
"Mitochondrial biogenesis and the decline of hypoxia, oxidative stress and toxin tolerance with age"
“线粒体生物发生以及缺氧、氧化应激和毒素耐受性随着年龄的增长而下降”
- 批准号:
250649-2012 - 财政年份:2014
- 资助金额:
$ 4.95万 - 项目类别:
Discovery Grants Program - Individual
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