Although asthma is typically thought of as a single disease, our recent data suggest that not all asthma is the same. These observations suggest that asthma treatment could be improved by targeting specific therapies to the specific groups of patients that will respond to them. Unfortunately, we do not currently have methods to distinguish these different groups of patients. The overall goal of this grant is to develop novel methods to identify these groups of patients with asthma. We propose to do this in three ways, by developing methods to: 1) distinguish patients with different types of underlying inflammation, 2) distinguish patients with chronic structural changes in the airway (remodeling) from those without such changes and 3) distinguish patients who will respond well to inhaled corticosteroids from those who will not. Some patients may have asthma due to allergic inflammation caused by over-activity of interleukin-13 [IL13], a biological mediator that clearly causes an asthma-like condition in mice. Indeed, specific blockers of IL13 are being developed as a therapy for asthma. However, our data show that only half of patients with asthma have over activity of IL13, and currently there is no way to distinguish which patients these are. Therefore, the first aim of this grant is to develop markers of """"""""IL13 driven"""""""" asthma by studying the expression of genes in lung tissue and blood of patients using gene expression microarrays. The results will help target IL13 blocking therapy to those who will benefit. Some patients with asthma have chronic structural changes in the airway known as airway remodeling. This remodeling is thought to cause chronic airway narrowing. However, it is currently impossible to determine who has remodeling without a biopsy.
In aim 2 of this grant, we propose to measure remodeling in biopsies using a technique called """"""""stereology"""""""" and identify markers of remodeling based on gene expression in the lung and blood. We believe the results will establish better methods for studying airway remodeling in patients and will identify genes that cause remodeling. Finally, some patients with asthma respond very well to inhaled corticosteroid therapy, whereas others do not. The reasons for this are poorly understood and it is difficult to predict who will respond. Furthermore, patients who do not respond well to inhale corticosteroids can be difficult to manage.
In aim 3 of this grant we propose to identify markers of response to inhaled corticosteroids in asthma by applying gene expression microarrays to lung and blood cells as part of 2 clinical trials of inhaled steroids. These results will help identify patients who are resistant to corticosteroids. They will also identify genes that contribute to steroid resistance. Indeed, in each of these aims, the markers that we identify may also be causes of the inflammation, remodeling, corticosteroid resistance from which some patients with asthma suffer. Therefore, in addition to studies performed in human subjects, we propose to use cell culture models to study whether these genes can cause these problems. The ultimate goal of these cell culture studies is to identify new therapies for asthma.
Asthma is a common disease, affecting ~7% of the adult US population, but not all asthma is the same. This project is directly relevant to public health in that it will establish methods to identify the different types of asthma and help target specific asthma therapies to the patients who will benefit from them the most. In addition, these genome-wide studies, combined with cell culture studies, have the potential to identify unsuspected causes of asthma that could be targets for new therapies directed at inflammation, airway remodeling and steroid-resistance in asthma.
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