Non-Canonical Pathways Towards Rescue from Neurodegenerative States

Neurodegeneration research has mainly focused on the brain and the compromised neurons and circuits. Nevertheless, evidence points to roles for body-to-brain connections (via peripheral nervous system and/or a compromised blood-brain-barrier, BBB) and inflammation mediated by non-neuronal brain cells. We plan to focus on (1) understanding the role of the periphery in propagating neurodegeneration; and (2) engineering non-invasive gene-delivery tools that specifically target non-neuronal brain cells relevant to neurodegeneration, such as immune cells and brain endothelial cells comprising the vasculature, since an impaired BBB can initiate and/or precipitate neurodegeneration. We will also contribute methods that enable the biodistribution of systemically delivered molecules (such as whole-body tissue-clearing and labeling) to aid understanding and prevention of neurodegeneration.