Juan Angel_Diversity Supplement: R01 NS120895

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Abstract Astrocytes are versatile glial cells that regulate diverse processes in the central nervous system (CNS). Roles for astrocytes during disease are complex and include both protective and pathologic functions. Recently, distinct astrocyte activation states have been described, though the molecular mechanisms that govern astrocyte polarization during neurotropic viral infection are not well understood. Here, we propose that receptor-interacting protein kinase-3 (RIPK3) is a previously unappreciated driver of inflammatory astrocyte activation during viral infection of the CNS. While roles for RIPK3 in programmed cell death have been extensively characterized, our published work has described pleiotropic, cell death-independent functions for this pathway in the coordination of protective neuroinflammation during viral encephalitis. In preliminary studies, we now show that RIPK3 signaling in astrocytes is required for survival and virologic control following challenge with Zika virus, an emerging neurotropic pathogen of global concern. Using a combination of novel mouse genetic tools, we will elucidate roles for RIPK3 signaling in astrocytes by 1) Defining profiles of expression, activation, and antiviral function for astrocytic RIPK3; 2) Determining roles for astrocytic RIPK3 signaling in coordinating neuroinflammation; and 3) Defining key substrates and transcriptional outputs of RIPK3 signaling in astrocytes. Together, our studies promise to identify new molecular mechanisms governing protective neuroimmune function during viral encephalitis.