This K23 application proposes a program of patient-oriented research training and two clinical studies which will apply novel techniques to study the mechanisms of airway hyperresponsiveness, one of the cardinal clinical features of asthma. The long-term objective is to address persistent gaps in knowledge that prevent the development of novel and specific treatments of airway hyperresponsiveness in asthma. The proposed approach will apply recently developed techniques for morphometry (design based stereology), cell isolation (laser capture microdissection), and gene expression analysis [two-step real time polymerase chain reaction (PCR)]. Application of these techniques to bronchial biopsy specimens obtained during bronchoscopy will make possible, for the first time, the study of gene expression in airway smooth muscle cells isolated from well characterized human subjects.
The specific aims of the proposal are to: 1) determine the relationship between airway smooth muscle morphometric measures and the physiologic measures of airway function, airway hyperresponsiveness [PC (20)] methacholine) and airway obstruction [(FEV (1)]; 2) determine if the gene expression profile of airway smooth muscle cells in asthma is characterized by increased expression of structural and contractile proteins, regulated by the transcription factor, serum response factor (SRF), and thought to be important in determining smooth muscle contractility in vitro; and 3) examine the relationship between corticosteroid-induced improvements in airway hyperresponsiveness in asthmatic subjects and changes in smooth muscle cell gene expression in order to identify important mediators of airway hyperresponsiveness. Because their method for analysis of gene expression will allow the analysis of many genes, they also plan to use gene expression array data and emerging in vitro data to guide them in the identification of other potential candidate genes for airway hyperresponsiveness. They propose two clinical studies: 1) a cross-sectional study comparing smooth muscle morphometry and gene expression in asthmatic subjects with mild airway hyperresponsiveness, more severe airway hyperresponsiveness, and non-asthmatic control subjects; and 2) a randomized placebo-controlled trial of inhaled corticosteroids in mild asthmatics comparing gene expression changes between groups, and determining the relationship between gene expression and PC20 within the intervention group. The candidate will complement these studies with a curriculum of advanced training in methods for the design and analysis of gene expression studies in human subjects.
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