""""""""Severe asthma"""""""" consists of a population of asthma patients with persistent symptoms despite the use of high doses of inhaled or oral corticosteroids who frequently utilize healthcare resources. Severe asthma represents a heterogeneous subset of asthma patients who are at risk for adverse outcomes. In some patients, frequent and severe symptoms occur despite aggressive therapy. However, in some patients severe disease may in part reflect limited access or adherence to appropriate asthma care. Other patients with asthma may have fixed and progressive reductions in pulmonary function that do not reverse completely either after intense acute or long-term therapy. These abnormalities in lung function may reflect structural changes in the airways that have been classified as """"""""airway remodeling"""""""". The varied clinical patterns found in severe asthma may reflect genetic differences that regulate bronchial inflammation and their environmental interactions, as well as that affecting intrinsic pathophysiologic abnormalities in the lungs and the tendency to airway remodeling. The purpose of this proposal is to select and phenotype 200 patients (100 Caucasians and 100 African-Americans) with severe asthma and contrast them with a cohort of patients with mild persistent asthma who have already been evaluated in our laboratories. We will determine whether there are differences in patterns of cellular and cytokine mediated inflammation between patients with severe versus mild asthma by using investigative bronchoscopy to obtain secretions (BAL) and tissue (biopsy) from 80 patients with severe asthma and 40 with mild asthma. Measurement of cytokines and cellular responses will be made in order to determine differences in cellular responses and inflammatory indicators. We hypothesize that differences that cause severe disease are produced by altered inflammatory responses that are related at least in part to sequence variants (polymorphisms) in genes that regulate inflammation in the airways. We also hypothesize that a subset of patients develop severe asthma because of genetic differences that modulate responses to pharmacologic agents. We will determine whether sequence variants in genes that regulate inflammation, cellular responses, tissue injury and repair or response to a specific therapy are more frequently associated with severe asthma by genotyping single nucleotide polymorphisms (SNPs) in 25 candidate genes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-H (S1))
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Noel, Patricia
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Wake Forest University Health Sciences
Internal Medicine/Medicine
Schools of Medicine
United States
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