Grant: Doctoral Research Award: Canada Graduate Scholarships

Allergic disorders can range from mild cases of asthma to severe reactions such as anaphylaxis, and while treatments exist, they have varying efficacies depending on the population and allergy type. Allergic diseases are also becoming increasingly prevalent worldwide, with asthma and allergic rhinitis affecting over 300 million and 400 million people worldwide, respectively. These numbers are continuing to rise, so identifying additional therapeutic targets to combat these diseases is crucial. Inflammation during allergic disease is primarily mediated by mast cells, a type of tissue-resident immune cell. Mast cells contain numerous granules that contain various pro-inflammatory mediators including histamine and cytokines. Mast cells release these mediators in a process called degranulation, which depends on the activity of Rho GTPases, a class of signalling proteins. Rho GTPases are regulated by proteins called RhoGDIs. Two forms of RhoGDIs, RhoGDI1 and RhoGDI2, are present in mast cells and have been proposed to act as both inhibitors and promoters of Rho GTPase activity. However, their specific role in mast cell degranulation is unknown. In cell culture, I found that reducing levels of RhoGDI1 or RhoGDI2 in mast cells results in increased active Rho GTPase levels and subsequently increased degranulation levels. Based on these results, I hypothesized that RhoGDIs act as inhibitors of Rho GTPases during mast cell degranulation. My work intends to determine the molecular mechanisms behind this process, and if any aspects can be modulated or mimicked to prevent excessive degranulation of mast cells as potential therapies for allergies.