Molecular Regulation of Microglia Behavior

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DESCRIPTION (provided by applicant): Neuronal injury and degeneration are accompanied by inflammatory responses from the innate immune system. Central nervous system tissues have highly specialized innate immune responses mediated primarily by microglia, the resident macrophage population. Microglia invade the CNS early in embryonic development and are a highly specialized cell of myeloid origin with unique features and functions. One of those unique aspects of microglia behavior is that are normally quiescent, expressing few markers associated with other specialized macrophage behaviors. Like their macrophage cousins however, microglia can respond to changes in the CNS environment by adopting a variety of behaviors. When microglia respond to changes in their environment, they can perform functions associated with "classical" macrophage activation that evolved as effective responses to bacterial and viral pathogens as well as those involved in quelling an inflammatory response or participating in the process of tissue repair. Currently, there is debate regarding which microglia functions dominate during acute or chronic injuries and no clear method of experimentally inducing microglia to adopt a specific set of behaviors. We have identified p53 as a transcriptional regulator that promotes behaviors associated with classical activation in microglia while p53 deficiency yields gene expression patterns associated with anti-inflammatory and tissue repair functions in microglia. One mechanism by which p53 influences microglia behavior was identified as negative regulation of a second transcription factor, c-Maf. The c-Maf transcription factor is a known regulator of both lymphocyte and myeloid cell differentiation, generally observed to promote the anti-inflammatory/tissue repair arm of both the innate and adaptive immune system. This proposal will further explore these discoveries by first demonstrating that the function of c-Maf in macrophages is recapitulated in microglia, second identifying the molecular mechanisms by which p53 influences c-Maf expression and third determining if p53 modulates microglia behaviors in vivo using the Cre/lox system to inactivate p53 in a time and cell type specific fashion.