Creation and Characterization of Lineage-Restricted Stat5B KO Mice

Project Summary Signal transducers and activators of transcription (Stats) are transcription factors with critical roles in the immune and endocrine systems. While there is considerable knowledge of Stat- mediated gene control, we know far less about lineage-restricted Stat functions. Understanding cell-specific actions is necessary for progress in diseases impacted by Stat dysfunction – including cancer, infertility, metabolic disorders, immunodeficiency, and chronic inflammation. We have evidence that Stat5B is pivotal for mast cell function. Like several other Stat proteins, Stat5B forms dimers and tetramers. We find that Stat5B dimers and tetramers have some similar and some opposing functions. Dimers and tetramers promote cytokine secretion. But while Stat5B dimers promote mast cell histamine production and cell migration, tetramers appear to inhibit both functions. These data are consistent in vitro and in a model of systemic anaphylaxis. Therefore, our hypothesis is that Stat5B dimers and tetramers have distinct effects on mast cell function, with tetramers often limiting the effects of dimers. Understanding this fundamental biology has considerable translational potential. Therefore, we propose creating several strains of mice that allow lineage-specific deletion of Stat5B or selective expression of a Stat5B mutant that can form protein dimers but not tetramers. These mice will make possible detailed studies of Stat5B, allowing us to understand how this protein contributes to the function of specific cell types.