Grant: Project Grant

The brain demands enormous amounts of energy and oxygen to maintain proper function. The smallest blood vessels in the brain, called capillaries, meet this demand as the primary sites of sugar and oxygen exchange. However, because these blood vessels are so small and have low pressure, they are naturally prone to becoming stalled or obstructed by red and white blood cells which can stick to capillary walls. Recent studies have directly implicated capillary stalling as a key contributor to blood flow and neurological (thinking) problems associated with Alzheimer disease, diabetes and stroke. Calcium activity within the cells that line blood vessels, called endothelial cells, is central to their function. Calcium serves as a nexus for multiple signalling pathways that can directly affect proteins that regulate endothelial "stickiness" or affect blood flow via smooth muscle cells/pericytes that enwrap vessels. We have exciting preliminary data showing that endothelial calcium waves play a critical role in preventing capillaries from becoming stalled, at least in the un-damaged brain. Thus, the primary goals of this research proposal will be threefold. First, we will image the living mouse brain to further understand the relationship between endothelial calcium waves and capillary blood flow. Second, we will dissect how endothelial calcium waves promote re-flow in blocked capillaries. Third, since stroke (which is caused by an obstruction to a very large vessel) is associated with poor blood flow in capillaries, we will manipulate endothelial calcium waves to see if we can improve blood flow and functional recovery. Collectively, these studies will offer unprecedented insights into the fundamental role that endothelial calcium waves play in regulating brain blood flow, as well as potentially offer new therapeutic approaches for recovering brain function after injury.