Exposing the glial metabolism - common link to brain damage

European population is rapidly aging. While it was commonly believed that brain aging leads to neuronal loss, recent studies found that instead the volume of white matter (WM) decreases and WM lesions develop with age. WM degeneration is also a hallmark of multiple neurological disorders including Alzheimers disease or multiple sclerosis. Understanding cellular responses to WM injury is therefore critical for design of regenerative therapies of central nervous system (CNS). The European population is also increasingly overweight. Obesity is associated with higher risk of multiple sclerosis and other neurological diseases and leads to systemic low-grade inflammation modulating functions of the immune cells. While this paradigm has been extensively studied in peripheral tissues, effect of diet on microglial states in CNS is poorly understood. I hypothesise that high-fat diet disrupts metabolic response of microglia to WM injury and impairs regeneration. My proposal aims to identify diet-altered microglial pathways and how to target them for promoting recovery after injury. For this goal, I will use the single cell and spatial transcriptomics to characterize in detail how WM injury and obesity alters cellular phenotypes. However, currently no method can link the metabolic state of the cell with its transcriptome. I will establish method that combines metabolic measurements with single cell RNA-Seq in mouse models of high-fat diet and demyelination. In addition, I propose to integrate spatial transcriptomics with electron microscopy as an innovative approach to visualize lipid-loaded microglia and link their morphology to the transcriptomic state. This project will provide critical new knowledge of mechanisms of WM repair. The fellowship will allow me to become expert in applying and developing genomic technologies to devastating neurological disorders, and deepen leadership and management skills to achieve my career goal of becoming independent investigator.