Astrocyte Response to Glymphatic Shear Force

About This Grant

Our overall hypothesis is that astrocyte endfeet at perivascular regions act as sensory cells, responding to shear forces along the glia limitans. We propose to quantify the sensitivity of mouse and human astrocytes in basal and reactive states to these forces and to determine the extent to which the transduction mechanisms that we have identified contribute to brain hemorrhage and cerebral edema. For this, we will use a combination of techniques that include Ca2+ imaging in microfluidics devices to quantify forces and responses, pharmacological and genetic deletion to identify molecular players, imaging of brain slices to gauge response to osmotic stimuli, and super-resolution microscopy to localize endfoot proteins and their colocalization with each other in regions of infarct. These studies are based on our recent publication showing that mouse astrocytes are highly sensitive to shear stress when the mechanosensor Piezo1 is activated, and are designed to quantify this sensitivity and how it can be modulated by other factors. In addition to evaluation of forces that astrocyte endfeet feel, these studies are expected to have high impact in the understanding of conditions that regulate glymphatic flow and normally clear amyloid and other debris from brain extracellular space. Such understanding could ultimately lead to conditions that restore normal glymphatic function in aging and neurological disease such as Alzheimers.