IRS phosphorylation by type I IL-4R signaling and its role in allergic disease

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DESCRIPTION (provided by applicant): The long-term career goal of the Candidate is to become an independent scientist whose lab is at the interface of basic molecular and human patient-based research. The Candidate has a strong desire to become an expert on all aspects of the biology of interleukin (IL)-4 signaling in human cells and how these pathways lead to lung diseases, such as asthma. To achieve these career and research goals, three Specific Aims are proposed, each customized to allow the further necessary research training and career development and, finally, to launch her independent career. The broad aim of the proposed research is to define the signaling and functional responses following engagement of type I IL-4 receptors by IL-4 and to understand how these signaling pathways contribute to the inflammatory process in diseases such as asthma. To this end, the role of unique components of the type I IL-4 receptor (gammaC chain and JAK3) in mediating strong tyrosine phosphorylation of IRS-2, a key adaptor molecule in this pathway, will be defined. The type II IL-4 receptor elicits only weak IRS-2 phosphorylation. Three genes, characteristic of alternatively activated macrophages and associated with chronic remodeling of the lung, were significantly augmented after IRS-2 activation through type I IL-4 receptors. Since activation of IRS-2 is critical for the enhanced expression of these genes, the mechanisms that serve to negatively regulate the tyrosine phosphorylation of IRS-2 in response to lL-4 will be delineated. The SOCS proteins, serine phosphorylation of IRS-2 and IRS-2 acetylation will be examined as candidate mechanisms. Thirdly, the role that type I IL-4 receptor signaling plays in allergic disease will be assessed by determining receptor component expression, IL-4 signaling and negative regulation of lRS-2 phosphorylation in several cell types from allergic and normal donors. The mechanisms by which these changes occur in allergic cells will be determined. Revealing the molecular mechanisms of type 1 IL-4 receptor signaling and downregulation of IRS-2 phosphorylation by these studies will be crucial to rational design of therapies for allergic diseases, such as asthma and allergies.