Evaluating the immunomodulatory role of circular RNAs in microglia

Neuroinflammation is common in several neurodegenerative diseases, with brain immune cells, specifically
microglia, being a main driver of the inflammatory process. Understanding what triggers microglial activation and its pathways will lead to a better knowledge of inflammatory mechanisms involved in neurodegenerative disease pathology. Circular RNAs (circRNAs) have been studied extensively in the peripheral immune system due to their ability to induce innate immune responses. Because circRNAs are enriched in the brain and exhibit age-accumulation in multiple species, there has been a successful effort in the past years to identify circRNAs unique to neurological diseases. However, the function of most circRNAs, including their contribution to
immunomodulation in brain cells, remains unknown. In this project, my aim is to study the functional relevance
and contribution of circRNAs in immunomodulatory activity of microglia in the brain. First, I will determine the
functional consequences of circRNA uptake in microglia, specifically investigating human microglial activation
and innate immune signaling induction after circRNA uptake and examining the effect of different circRNA
modifications on microglial function in initiating an immune response. I will then investigate the mechanism of
circRNA uptake in microglia by determining the genes that regulate circRNA uptake, and further investigate the
characteristics of circRNA uptake by human microglia. Together, this work will expand our current knowledge
about circRNA functionality in diseased brains, and establish new research and therapeutic approaches using
circRNAs and microglia to address immunomodulatory activity in neurodegenerative disease pathology.