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

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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 and to become an expert on all aspects of the biology of interieukin (IL)-4 signaling in human cells and how these pathways lead to lung diseases, such as asthma. To achieve these goals, three Specific Alms were proposed, to allow the further necessary research training and career development and to launch her independent career. The proposed K99 career/research training goals have all been met. The broad aim of the proposed research is to define the signaling and functional responses following engagement of type I lL-4 receptors by IL-4 and how these signaling pathways contribute to inflammation in diseases such as asthma. The first Aim achieved during the K99 phase defined a 5 amino acid (aa) sequence interval within the DC chain, one component of the type I IL-4 receptor, that mediated strong tyrosine phosphorylation of IRS-2, a key adaptor molecule in IL-4 signaling. The interval lay between aa318 and 323 and correlated with the association of activated JAK3 in the signaling complex. 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 goal of the second Aim to be carried out in the ROO phase will be to delineate the mechanisms that serve to negatively regulate the tyrosine phosphorylation of IRS-2 in response to IL-4. The SOCS proteins and serine phosphorylation of IRS-2 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 regulatioii of IRS-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 I IL-4 receptor signaling and downregulation of lRS-2 phosphorylation by these studies will be crucial to rational design of therapies for allergic diseases, such as asthma.