IMMUNOGENETIC DISEASE-ALLERGIC INFLAMMATION TO AIRWAY REMODELING IN 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 overall goals of this developmental project are to understand the genetic determinants of susceptibility to asthma among Asians and Pacific Islanders and to evaluate the consequences of this susceptibility on airway remodeling. Specifically, we will examine in our population of asthmatics the following hypotheses: 1. Variant polymorphisms in the genes which encode the alpha chain of the interleukin 4 (IL-4) receptor and the interleukin 10 (IL-10) promoter are associated with increased T-helper type 2 (Th2) response, which is a specific inflammatory response to asthma. 2. Activation of the Th2 pathway is associated with differential transcription of genes implicated in fibroblast/myofibroblast proliferation and activation, leading to airway remodeling. 3. Products of these genes are differentially expressed in airway cells and tissues of asthmatic subjects who have functional evidence of airway remodeling. These hypotheses will be explored by fulfilling the following specific aims: Specific aim 1: Identify cytokine and growth factor genes that are most highly expressed at the transcriptional level in circulating leukocytes of patients with allergic asthma and airway remodeling, compared to patients who are neither allergic nor asthmatic. Specific aim 2: Elucidate the association between variants in the IL-4 receptor alpha and IL-10 promoter genes and measure the activation of the Th2 pathway in asthmatic and non-asthmatic patients. Specific aim 3: Characterize the baseline expression of genes involved in the formation of collagen and other matrix proteins in cultures of human airway fibroblast cell lines and primary cultures of human nasal fibroblasts Specific aim 4: Characterize and confirm the transcriptional response of genes that encode extracellular matrix proteins or apoptosis-related genes to cytokines identified in specific aim 1.