The Contribution of Microglia to Neurodevelopmental Dysfunction in Down Syndrome - PROJECT SUMMARY Down Syndrome (DS), caused by trisomy of chromosome 21 (Chr21), is the most common chromosomal condition with over 200,000 individuals carrying the diagnosis in the US alone. DS, which is a multisystem disorder, is notably characterized by intellectual and developmental disability as well as immunological dysfunction. The association between the cognitive and immune disruption observed in patients with DS remains to be elucidated. Based on mounting evidence implicating i) important microglial contributions to neurodevelopment ii) microglial activation in individuals with DS and iii) our preliminary findings of DS microglial inflammation and differential impact on brain environment in our models, this proposal is built around the central hypothesis that microglia contribute to the neurodevelopment of DS. The contribution of innate immune activation to DS pathology is poorly understood. Individuals with DS have increased incidence of both infection and multiple autoimmune disorders. Chromosome 21 carries the genes that encode four interferon (IFN) receptors in addition to other IFN response elements, which is proposed to contribute to the prominent immune dysfunction in DS. Microglia are a key regulator of the neuroimmune response and are modulated by IFN activation. Therefore, the project goal is to test the hypothesis that microglial activation related to IFN signaling contributes to neurodevelopmental phenotypes in vitro (Aim 1), and in a xenotransplantation model in vivo (Aim 2) resulting in microglia pathology and neuropathological and DS-associated behavioral defects. This microglial pathology will be further dissect in Aim 3, where the impact of DS on microglial heterogeneity and genome architecture will be queried to identify candidate transcription factors driving microglial dystrophy in DS. The long-term goal is to identify the contribution of microglia pathology to the DS neurodevelopmental phenotype, allowing for the elucidation of potential novel therapeutic targets of the most common cause of developmental and intellectual disability in the US. The proposed research will take place in the Coufal and Glass laboratories at UC San Diego. The Coufal lab lends expertise in human induced pluripotent stem cell models of neuroimmunology, and the Glass lab has extensive experience in macrophage gene regulation. Through graduate coursework, mentorship, and hands- on learning, Genevieve will gain experience in approaching large datasets from a quantitative prospective and will learn cutting edge wet lab and behavioral neuroscience techniques; these skills will be valuable for the completion of the proposed research and for Genevieve’s future career as a physician-scientist.
