Investigating the Regulation of the Oxidative Stress Response

研究氧化应激反应的调节

• 批准号: RGPIN-2019-06317
• 负责人: Kubiseski, Terrance
• 金额: $ 2.33万
• 依托单位: York University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=738836
• 关键词: Investigating; Regulation; Oxidative; Stress; Response

Oxygen radicals (or reactive oxygen species) are an unfortunate by-product that occur both internally (from normal cell metabolism) and externally in our environment and have been implicated in many age-related disease's including Parkinson's disease, Alzheimer's and cancer. Over time, as one ages, there is an accumulation of damage done to cells, proteins and DNA due to reactive oxygen species. Pathways have evolved to become activated in cells to limit the damage from reactive oxygen species by generating anti-oxidant proteins that remove them and limiting the exposure of an organism to long-term damage. We propose to look at one pathway genetically by using C. elegans as a model organism that regulates production of anti-oxidant proteins. The "worm" has proven to be very useful for genetic studies because it is easy to grow, it is small enough for characterization of every individual cell in the organism (@1000 total cells) and we can manipulate it by safely adding modified genes or creating mutations. Many genes in humans, especially those involved with important biological processes such as protection against reactive oxygen species, are present in C. elegans. Using the worm, in our previous work we discovered the possibility that two proteins, VAB-3 and ZTF-17 may both be important gene regulators and involved in oxidative stress response that help prevent damage associated with aging. This proposal involves using the worm as a tool to investigate the roles of these two proteins play in regulating gene expression of anti-oxidant proteins, using genetic mutants that prevent the production of these two proteins. The goal is to establish if VAB-3 and ZTF-17, and by analogy their human counterparts, play a positive role in expressing anti-oxidant proteins and reduce the damage of oxygen radicals. We are interested in determining what other proteins that interact with ZTF-17 to regulate it and help carry out its function. Thus, another goal of this project proposal is to identify new proteins that work with ZTF-17 with the use of a new innovative technique called BioID and help us to better understand the oxidative stress response. The benefit of this research will be to gain a better understanding of how animal cells deal with damage caused by destructive compounds like oxygen radicals. Once a better understanding of these protective mechanisms is achieved, appropriate targets for therapeutic intervention become clearer and strategies can be developed that promote anti-oxidant protein production, to reduce or prevent the damage caused by these compounds.

氧自由基（或活性氧簇）是一种不幸的副产品，在我们的环境中既存在于内部（来自正常细胞代谢），也存在于外部，并且与许多与年龄相关的疾病有关，包括帕金森病、阿尔茨海默病和癌症。随着时间的推移，随着年龄的增长，由于活性氧对细胞，蛋白质和DNA造成的损害会积累。细胞中的通路已经进化为被激活，以通过产生去除活性氧的抗氧化蛋白并限制生物体暴露于长期损伤来限制活性氧的损伤。 我们建议用C.线虫作为模式生物，调节抗氧化蛋白的生产。“蠕虫”已被证明对遗传研究非常有用，因为它很容易生长，它足够小，可以表征生物体中的每个细胞（@1000个总细胞），我们可以通过安全地添加修饰基因或创建突变来操纵它。人类的许多基因，特别是那些与重要的生物过程有关的基因，如保护免受活性氧的侵害，都存在于C。优美的利用蠕虫，在我们之前的工作中，我们发现了两种蛋白质VAB-3和ZTF-17可能都是重要的基因调节剂，并参与氧化应激反应，有助于预防与衰老相关的损伤。该提案涉及使用蠕虫作为工具来研究这两种蛋白质在调节抗氧化蛋白基因表达中的作用，使用防止这两种蛋白质产生的遗传突变体。目标是确定VAB-3和ZTF-17以及它们的人类对应物是否在表达抗氧化蛋白和减少氧自由基损伤方面发挥积极作用。我们有兴趣确定哪些其他蛋白质与ZTF-17相互作用以调节它并帮助执行其功能。因此，该项目提案的另一个目标是使用称为BioID的新创新技术鉴定与ZTF-17一起工作的新蛋白质，并帮助我们更好地了解氧化应激反应。 这项研究的好处将是更好地了解动物细胞如何处理氧自由基等破坏性化合物造成的损害。一旦对这些保护机制有了更好的理解，治疗干预的适当目标就变得更加明确，并且可以开发促进抗氧化蛋白产生的策略，以减少或预防这些化合物引起的损伤。