This proposal is focused on defining the cellular mechanisms that regulate key aspects of human eosnophil biology, including cell sensitization (priming), chemotaxis, survival and proinflammatory/cytotoxic activities. Eosinophil recruitment and activation are characteristic of airway disorders such as allergic disease, and these cells exhibit multiple effector activities that contribute to the tissue damage and fibrosis associated with asthma. In this regard, interleukin-5 (IL-5) and related cytokines are critical for modulating eosinophil degranulation, migration, gene expression, and viability. Also, low levels of IL-5-family cytokines induce the enhanced responsiveness of eosinophils to a variety of secondary agents, such as chemoattractants. Although this priming process is important for eosinophil biology, the associated signaling events are not well understood. However, we are uniquely positioned to carefully dissect the role of specific signaling events in modulating blood and airway eosinophil function. Capabilities enabling this research include: a) Routine access to large numbers of highly purified human blood and airway eosinophils. b) Our ongoing identification of key signaling molecules mediating IL-5 and chemoattractant action in blood and airway eosinophils, e.g:, Ras, the MAP kinases (ERKs 1 and 2), the transcriptional regulators STATs 3 and 5, the beta-arrestin adaptor molecules, and the survival-associated kinase Pim-1. c) Our development of essential molecular and pharmacological methods for analyzing cytokine/chemoattractant signaling in human eosinophils. These abilities allow us to test the hypothesis that eosinophil regulation by IL-5 involves the aforementioned signaling molecules, and that their regulation is important for priming blood eosinophils to become responsive to chemoattractants. The following Aims are proposed: 1) Define the mechanisms of IL-5- mediated priming of chemoattractant-induced events in human blood eosinophils using the activation of the MAP kinases (ERK1/ ERK2) as a cellular marker. 2). Determine the biological relevance of IL-5-dependent activation of specific receptor/signaling complexes (Ras/ERK, tyrosine kinases, Deta-arrestins) and the integrity of membrane microdomains in the control of blood and airway eosinophil function. 3) Test the concept that Jak-STAT-dependent pathways are linked to IL-5-mediated regulation of human eosinophil priming and function, including Pim-1 expression,.cell survival and chemoattractant-induced responses.
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