Bioactive Material Interventions for Ischemic Stroke

PROJECT SUMMARY Stroke is a leading cause of long-term disability worldwide, and a major consequence of stroke is the doubled risk of new (incident) dementia for at least a decade afterwards. Ischemia-induced neurodegeneration is a leading culprit for dementia development and there are currently no therapies to treat or prevent dementia in the 7 million stroke survivors in the US despite the need. The neurogliovascular unit (NVU) is comprised of glia (astrocytes), mural (pericytes), and endothelial cells. Following ischemia there is breakdown of the NVU and a loss of cells (astrocytes and pericytes) responsible for maintaining barrier function in and around the stroke scar. Urokinase plasminogen activator (uPA) plays a large role in encouraging astrocytes to extend their processes following an ischemic injury. This process occurs naturally but could be delayed in aging. Platelet- derived growth factor B (PDGFB) is a top candidate for a therapy as it is critical for recruiting pericytes to seal vessels and inhibits early angiogenesis. Our goal is to develop a therapy for chronic post-stroke dementia, via development of an injectable hydrogel with an integrated uPA motif, and plasmid DNA (pDNA) PDGFB- lipoplexes than will be loaded into the gel for delivery into the stroke scar. I hypothesize neurovascular integrity will be restored through local uPA interactions promoting astrocytic endfeet coupling and PDGFB release encouraging pericyte coverage. Emerging data has revealed a prolonged disruption of neurovascular integrity and appears correlated to greater cognitive decline in humans. We believe restoring neurovascular function will support improved cognition at chronic timepoints following stroke. We aim to create a gel capable of sustained retention and cargo release to promote astrocyte and pericyte recruitment over a period for new vasculature to mature and demonstrate properties of the blood-brain-barrier. The efficacy of our gels and PDGFB-lipoplexes will be evaluated in a preclinical mouse stroke model, no treatment, delivery of injectable hydrogel without uPA motif, hydrogel with uPA motif, general hydrogel with control lipoplexes, general hydrogel with PDGFB- lipoplexes, hydrogel with uPA motif and PDGFB-lipoplexes. Analyses will span immunohistochemical, live animal imaging, and cognitive and behavioral testing. Along with my strong mentoring team at Stanford University, and external advisory team, we have created a career development plan to advance my scientific and academic and professional skillsets. Through this mentored training plan, the MOSAIC K99/R00 will prepare me to transition to a tenure-track faculty role.