Eosinophils are known to be involved in the pathogenesis of several diseases. These include allergic and parasitic diseases. Both eosinophil differentiation and maturation in the bone marrow, as well as the post-mitotic functional activation and prolonged survival of eosinophils in tissues occurs in response to cytokines. Several studies indicate only IL-5 is specific for eosinophils. Prior studies have demonstrated that IL-5 exerts its effect through a heterodimeric cell surface receptor which has a shared beta subunit and a unique alpha subunit. Both components are required for optimal signal transduction. Nothing is known of the molecular mechanisms for transcriptional regulation in the induction of eosinophil differentiation or the lineage-specific expression of the IL-5Ra gene by multipotential myeloid progenitors or the developing eosinophil.
The specific aims are to investigate the molecular mechanisms for transcriptional regulation of the IL-5Ra gene in eosinophil development.
Three specific aims are proposed: 1) What are the transcriptional and post-transcriptional mechanisms for eosinophil- specific expression of the IL-5R gene during the commitment of multipotential myeloid progenitors to the eosinophil lineage. 2) What are the transcriptional regulatory elements in the IL-5Ra promotor responsible for eosinophil -specific expression and up-regulation of expression by eosinophil-active cytokines? 3) What are the constitutive or cytokine -induced transcriptional factors which react with these control elements to regulate expression of the IL-5Ra gene? The applicant will clone and characterize trans-acting factors (starting with the EOS! Nuclear factor identified recently) that are shown to be critical for eosinophil -specific IL-5Ra gene expression and analyze the mechanisms regulating alternative splicing to produce soluble versus transmembrane forms of the receptor.
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