Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

B cells are immune cells best known for their role in producing immunoglobulins for specific defense against pathogens and abnormal self-cells. Like most cell types, B cell responses are controlled by integration of signals from the extracellular environment which are read by receptors on the cell surface. These signals are propagated inside the cell by signaling pathways that culminate in a particular cellular response. Some of these signals promote cell activation while others inhibit. The ability of our cells to balance these opposing signals appropriately in order to generate effective immune responses while avoiding tissue damage and autoimmunity is key to maintaining health. This project examines an important regulatory circuit in B cells that involves the lipid phosphatase SHIP, a regulator of an intracellular signaling pathway called the PI3-kinase pathway. SHIP negatively regulates B cell responses including cell proliferation and antibody production. SHIP and its associated inhibitory receptor are known to play a protective role in autoimmune diseases, leukemias, and allergic diseases. Given this important role and the fact that small-molecule activators of SHIP are now available, SHIP is emerging as a promising therapeutic target. This project aims to gain an understanding of how key signaling proteins influence SHIP activity and how the biochemical state of SHIP with respect to sub-cellular localization and post-translational modifications defines the functions of this protein. Dynamic spatio-temporal localization of SHIP and its regulators will be studied using cutting-edge live-cell imaging techniques. Post-translational modifications will be studied by Western Blotting and mass spectrometry. SHIP activity will be assessed by enzyme activity assays as well as by studying functional outcomes of structural changes. The results of these studies will provide crucial insight into how and when manipulation of SHIP activity might have a therapeutic benefit.