Grant: Discovery Grants Program - Individual

Overview My research program is about understanding the relationship between mitosis and genomic change. This is an important topic because each cell division has the potential to change the genome of future cells. Many components of human cells have been identified using genomic and biochemical approaches. We are now at the stage to study how these parts orchestrate an event as complex as cell division. I propose to do this by using new chemical mitotic inhibitors, which my laboratory has recently discovered. Methods and Previous Results My laboratory uses a multidisciplinary, chemical biology approach to study specific steps of mitosis. We chose to look for inhibitors in plant species from the prairie ecological zone. The rationale is that prairie plants are in competition with grazing animals, therefore the plants are likely to produce toxic chemicals to avoid being consumed by animals, such as buffalo (now cattle). Human cells are similar to cells from other mammals; therefore, these chemicals are likely toxic to human cells. We created a unique, annotated prairie plant library of 500 extracts from 149 species and 47 taxonomical families. My laboratory screened our library to identify extracts that altered cell function, especially mitosis. Our screen detected an anti-mitotic activity in crude extracts from the Blanket Flower (Gaillardia aristata), and we then collaborated with a Canadian chemist to purify the chemical responsible for the activity. We were the first to identify the anti-mitotic function of the chemical, Pulchelloid A (PulA), which is a member of the sesquiterpene lactone family. We found it arrests cells mitosis differently from other chemicals, including tubulin toxins. Our research points us to a mechanism in which one part of the cell stops dividing while another continues dividing, contributing to a distorted mitotic spindle and damaged DNA. These results have led us in two directions: 1. We are finding additional anti-mitotic inhibitors from species related to the Blanket Flower, in doing so, we have structurally related yet distinct chemicals 2. We are identifying the protein target(s) of this novel inhibitory chemical series We are proposing cell biology techniques, click-chemistry approaches, and to expand to the inhibitor chemical series to meet these objectives. Impact The benefits of our research including learning more about how human cells divide, which is a foundation to discover future medicines for proliferative diseases. We provide valuable multidisciplinary training experiences and focus on natural product science, which is under-developed in Canada, relative to Europe and Asia. Some of the plants we study are known to Indigenous communities, which creates opportunities to exchange scientific and Traditional knowledge. Finally, the prairie plant extract library is a resource for inhibitors to use in new projects and collaborations in Canada and globally.