The Role of Stat5 in Mast Cell Activation and Inflammatory Disease

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DESCRIPTION (provided by applicant): Mast cells are ubiquitous mediators of inflammation and have been studied for a number of years for their role in asthma, allergies, and anaphylaxis. However, in recent years, new data have emerged associating mast cells with a variety of other inflammatory disorders such as atherosclerotic heart disease, autoimmunity, host resistance to bacterial infection, and tumor angiogenesis. Hence, studying mast cell activation and function can have widespread implications including the development of new therapeutic strategies for inflammatory disease. Our proposal is to study the role of the transcription factor Stat5 in mast cell activation and function as well as to determine the importance of Stat5 in inflammatory disease. Our preliminary data collected from mouse bone marrow derived mast cells (BMMCs) demonstrate that Stat5 is a critical regulator of mast cell function, survival, and proliferation. These effects are most profound when examining the major contribution that Stat5 makes to FcepsilonRI signaling. After IgE crosslinkage, mouse Stat5-deficient BMMCs exhibit significantly reduced degranulation and almost complete loss of inflammatory cytokine secretion. Our data illustrate Stat5 as a potentially important therapeutic target for mast cell-related diseases, which warrants an investigation into the mechanisms controlling Stat5 activation and its consequences in vivo. Our proposal is segregated into these two issues. Our Aim 1 is to determine how IgE-mediated signals activate Stat5 in mouse and human mast cells, and the role of Stat5 in mast cell function. By gaining understanding of the Stat5 signaling pathway, we can uncover how new therapeutic strategies may intervene in this process. Aim 2 is to determine the importance of Stat5 to the mast cell response in vivo. We will determine whether Stat5 activation is critical in mouse models of passive systemic anaphylaxis (PSA) and airway hyperresponsiveness (AHR). In doing so, we can demonstrate how Stat5 can influence the inflammatory response in vivo, which can suggest its feasibility as a therapeutic target. PUBLIC HEALTH RELEVANCE: Mast cells are associated with a number of inflammatory diseases. By studying how mast cells function, we can further our knowledge of how mast cells can influence disease and be able to uncover new therapeutic targets.