MECHANISMS OF CORTICOSTEROID RESISTANT ASTHMA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objectives of this research project are to understand the immunologic and molecular mechanisms which distinguish "corticosteroid resistant" (CR) from "corticosteroid sensitive" (CS) asthma. Four specific aims are being pursued: First, to examine the role of cytokines in the pathogenesis of corticosteroid resistance, we will determine whether peripheral blood mononuclear cells (PBMC) and BAL cells from patients with CR asthma produce higher levels of IL-2, IL-4 and IL-13 than cells from patients with CS asthma. Second, to determiine whether peripheral blood corticosteroid resistance of T cells assessed by insensitivity of in vitro mitogen-driven responses to dexamethasone is a marker for severe asthma and if African-American asthmatics have a higher prevalence of corticosteroid resistance than other ethnic groups. Third, to identify the mechanisms(s) by which cytokines induce steroid resistance, we will evaluate glucocorticoid receptor (GCR) Beta and GCR Alpha in bronchoalveolar lavage (BAL) cells and PBMC from CR asthmatics, CS asmatics and normal controls. We will also define the intracellular location of GCR Alpha heterodimer formation. Finally, we will establish a bank of DNA from CR and CS individuals for the purpose of determining whether DNA sequence variants, identified in collaboration with a NIH-sponsored Pharmacogenetic Research Network Research Group, are associated with corticosteroid resistance.