Analysis of adaptive responses of astrocytes

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Reactive astrogliosis is associated with brain trauma, infections, ischemia, and neurodegeneration. As astrocytes become reactive, they undergo dramatic morphological and functional changes and both secrete and respond to a host of inflammatory mediators. We asked the question whether astrocytes also display adaptive plasticity of their responses, including priming and tolerance. In preliminary studies, we established that primary human astrocytes develop both “cytokine-tolerance” that depends on induction of RelB expression, its phosphorylation on Ser472, recruitment of the deacetylase SIRT1 and the lysine methyl transferase KMT1C and subsequent epigenetic silencing of cytokine genes. Surprisingly, we have also identified a set of intriguing and novel RelB-induced genes, which can be “primed” likely by an IRF1- and STAT1-dependent mechanism. We propose to test the hypothesis that cytokine- induced RelB drives gene expression programs regulating astrocyte adaptive responses and thus disease outcomes. We will 1) define the molecular basis of “cytokine-tolerance” and “priming” in astrocytes, and 2) d etermine the role of RelB in astrocyte activation in vivo.