PROJECT SUMMARY Microglia have a role in nearly every incurable psychiatric and neurodegenerative disorder, but of all the cell types in the brain, they remain the least tractable to study. Human cells in culture do not accurately recapitulate microglial biology, yet mice have demonstrably non-human neuroimmune responses to pathogens and disease models. Few methods are compatible with the highly reactive and tissue bound microglia, impeding all efforts to dissect their biology. Tools to resolve and manipulate these cells in vivo would accelerate neuroimmune research, from studies of basic biological function to disease mechanisms. In this proposal we refine several technologies for application in neuroimmune research. Magnetic Resonance Imaging (MRI), is one of the only modalities for noninvasive studies of the brain from mouse to human scales. MRI based signaling reporters offer the spatiotemporal resolution and sensitivity to detect even the rarest signals and each new sensor can change our view of neuroimmune signaling. Gene manipulations in microglia formerly required transgenics, but engineered human microglial precusor cells can be ectopically implanted to create human microglial chimeras, carrying new sensors and genetic models of disease. Finally targeted gene delivery to microglia is currently beyond our capabilities, but in nature, the Zika virus infects microglia, suppresses inflammation, and stimulates autophagy so expertly that almost half of infections go unnoticed. If this bioactivity could be safely refined, it would offer relief for neurodegenerative disorders from Parkinson’s to Alzheimer's disease. Together these technologies offer a comprehensive tool kit to engineer model systems, image disease progression and test therapeutic interventions in a humanized in vivo model, creating a path towards entirely new therapies for neurodegenerative disorders.

PROJECT NARRATIVE Microglia and neuroimmune signals have been implicated in nearly every incurable neurodegenerative disorder, but neuroimmune function remains difficult to define in model systems while microglia are nearly intractable in vivo. We are developing an essential tool kit to resolve and manipulate neuroimmune signals and cells including: non-invasive imaging of signaling reporters with MRI, a platform for engineering human microglia for in vivo implantation into humanized mice, and a novel viral vector for neuroimmune targeted gene delivery. Establishment of these tools will bring long overdue capabilities into neuroimmune research and accelerate the search for therapies for every neuroinflammatory pathology.