Investigating the Regulation of the Oxidative Stress Response

氧自由基(或活性氧物种)是一种不幸的副产物，在我们的环境中既发生在内部(来自正常的细胞代谢)，也发生在外部，并与许多与年龄相关的疾病有关，包括帕金森氏症、阿尔茨海默氏症和癌症。随着时间的推移，随着年龄的增长，由于活性氧物种对细胞、蛋白质和DNA造成的损害会积累起来。细胞中的途径已经进化为激活，通过产生抗氧化剂蛋白来去除它们，限制生物体遭受长期损害，从而限制来自活性氧物种的损害。*我们建议通过使用线虫作为调节抗氧化蛋白产生的模式生物来从遗传学上研究一种途径。这种“蠕虫”已被证明对遗传学研究非常有用，因为它很容易生长，它足够小，可以描述有机体中的每一个细胞(总共1000个细胞)，我们可以通过安全地添加修改的基因或创造突变来操纵它。人类中的许多基因，特别是那些参与重要生物学过程的基因，如防止活性氧物种，存在于线虫中。*使用线虫，在我们之前的工作中，我们发现两种蛋白质，VAB-3和ZTF-17可能都是重要的基因调节蛋白，并参与氧化应激反应，帮助防止与衰老相关的损害。这项建议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质的基因表达中所起的作用，使用阻止这两种蛋白质产生的基因突变。我们的目标是确定VAB-3和ZTF-17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，并通过类比它们的人类同行。*我们有兴趣确定哪些其他与ZTF-17相互作用的蛋白质来调节它并帮助实现其功能。因此，该项目提案的另一个目标是通过使用一种名为BioID的新的创新技术来识别与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。一旦更好地了解了这些保护机制，治疗干预的适当目标就变得更加明确，可以开发出促进抗氧化蛋白质产生的策略，以减少或防止这些化合物造成的损害。

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.*****