Investigating the Regulation of the Oxidative Stress Response

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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.