Grant: Operating Grant

About 200-300 newborn infants in Canada are affected by stroke each year. There are very limited treatment options and currently no pharmacological interventions. Reorganization and rewiring of connections between brain cells following injury can promote recovery. My lab has found a new protein called Pannexin 1 that regulates these changes. Pannexin 1 forms pores in the cell membrane that control passage of certain molecules. If we block these pores, or remove Pannexin 1 altogether, the cells extend processes called neurites, structures that are critical for rewiring of connections. Recently, we also discovered a physical interaction between Pannexin 1 and another protein called "collapsin response mediator protein 2" (Crmp2). Crmp2 promotes the growth of neurites. We predict that, during normal brain development, Panx1 'keeps the brakes' on neurite outgrowth by sequestering Crmp2. This prevents the formation of aberrant connections. When a stroke occurs in the newborn, recovery is hindered by Panx1 sequestration of Crmp2 because this limits rewiring. We therefore propose that blocking the Panx1/Crmp2 interaction will improve perinatal stroke recovery by enhancing rewiring. To investigate these predictions, we will perform a series of studies using a Pannexin 1 knockout mouse as well as a molecular tool we engineered to interfere with the interaction. Essentially, we will study how structural changes in cells during development and after injury are affected if Pannexin 1 is taken out of the equation entirely or if we prevent it from interacting with Crmp2. The primary goal of this research is to bridge key gaps in knowledge of the role of these proteins in creating structural changes in brain cells. Successful outcomes of this work will ultimately lay the groundwork for the development of novel therapeutics that could be used to improve health outcomes in patients affected by acquired brain disorders such as stroke and cerebral palsy.