Grant: CIHR Fellowship

A primary and often fatal consequence of stroke, traumatic brain injury, and other brain insults is edema: an increase in brain tissue water content. Cytotoxic edema is a component of this process and occurs when excess ions and water enter across the neuronal plasma membrane -the semi-permeable barrier separating the intra- and extracellular space. This increase in cell volume causes membrane swelling and ultimately results in cell death. Presently, the cascade of events by which neuronal swelling triggers cell death remains obscure. Preliminary evidence from Dr. Brian MacVicar's lab (the host) indicates that swelling triggers cell death by activating pannexins- a class of large transmembrane ion channels. Following activation, pannexins form large pores in the membrane and allow ions and small molecules to diffuse between the intra- and extracellular compartments. Consequently, pannexins can initiate cell death by collapsing the transmembrane electrochemical gradient and/or promoting the loss of essential cellular components. The precise mechanism by which swelling triggers the opening of pannexins is unknown. Interestingly, membrane stretch leads to the production of reactive oxygen species (ROS)-a group of harmful chemical agents that are implicated in activating pannexins. For the present proposal, I will test the hypothesis that pannexin activation is a crucial step underlying cell death during cytotoxic edema. Furthermore, I hypothesize that pannexins are activated by neuronal swelling through the production of ROS. These hypotheses will be tested in acutely prepared rat brain slices using advanced microscopy/imaging and electrophysiology techniques. As there are few effective treatments for edema, this research could reveal new avenues for therapeutic intervention following a variety of brain insults.