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Role of eosinophils in intestinal epithelial dysfunction

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Food allergic diseases are both more commonly recognized and occurring with an increased incidence. Histological hallmarks of certain food allergic diseases, such as eosinophilic gastroenteritis (EOG), include mucosal eosinophilia and deposition of eosinophil derived granule proteins (EDGPs) in the affected tissues. The most studied of these unique biologically active proteins such as major basic protein (MBP). Despite a large body of evidence describing clinicopathological features of EOGs, the role of eosinophils in the pathogenesis of these diseases is yet to be determined. While EDGPs likely play a role in allergic diseases, little is known about molecular mechanisms that EDGPs induce functional responses. Our preliminary data identified MBP influences two functional aspects of the intestinal epithelium. First, MBP diminishes epithelial barrier function likely through its impact on the tight junctional proteins, specifically occludin. Second, several layers of evidence show that MBP can induce epithelial TNF secretion and that the induction of this pro-inflammatory cytokine leads to disruption of barrier function. In combination, these results are particularly important since EOG is associated with impaired barrier function and altered cytokine production. Therefore, we hypothesize that EDGPs contribute to the pathogenesis of EOG by inducing epithelial proinflammatory cytokine production and diminishing barrier function. We present three focused specific aims to test this hypothesis: 1) define the impact of EDGPs on epithelial cytokine expression, 2) determine the influence of EDGPs on epithelial tight junction protein regulation, 3). Define the relevance of EDGPs in EOG utilizing EDGP null and "overexpressing" mice. In addition, we will define barrier properties and immunophenotypic features of human tissues affected by EOG. Long-term goals of these studies are the identification of specific diagnostic tests for EOGs and the development of novel eosinophil specific treatments.
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