The role of astrocyte subtypes in neurodegeneration

Astrocytes are a highly abundant cell type in the central nervous system. They perform critical homeostatic functions but respond to insults by undergoing a reactive transformation. By applying integrative single cell RNA-seq and genome-wide spatial transcriptomics I have recently discovered that astrocytes fall into discrete subtypes that occupy distinct spaces in the brain, and that each subtype undergoes a subtype-specific reactive transformation during brain inflammation. Key goals of my project are understanding how homeostatic, regionally-restricted astrocyte subtypes turn into specialized reactive subtypes in neuroinflammation and chronic neurodegeneration, particularly Alzheimer's disease (AD). I have already identified two subtypes relevant to neurodegeneration: 1.  An astrocyte super-responder subtype that is induced by type-I-interferons and is selectively present around amyloid plaque depositions. 2. I identified the transcriptomic identity of glia limitans superficialis astrocytes that cover the entire brain and spinal cord surface and can be described by a single gene, Myoc. Using scRNA-seq, spatial transcriptomics, advanced bioinformatic analyses as well as novel and established astrocyte-specific transgenic mice combined with functional in vitro assays, I will uncover the upstream-inducers and downstream functions of specialized astrocyte subtypes in order to identify novel therapeutic targets in neurodegeneration and neuroinflammation.