Asthma is characterized by allergic airway inflammation and airway remodeling which underlie the clinicalcharacteristics of airflow limitation, bronchial hyperresponsiveness, and susceptibility to exacerbation.Important questions remain for how asthma develops, the mechanisms of allergen sensitization, and thefactors that contribute to the persistence of asthmatic airway changes over a lifetime. Here we proposeclinical studies to investigate fundamental questions about the role of chitinases and TGFp in initiating andperpetuating allergic asthma. We will combine comprehensive genetic studies with detailed translationalstudies to address hypotheses for how polymorphisms in chitinase and TGFp pathway genes influenceallergen sensitization, asthma susceptibility and expression of asthma-related phenotypes.
Aim 1 willdetermine the independent and dependent effects of genetic variants in chitinases (AMCase/CHIT1) onsensitization to fungal aeroallergens and other asthma outcomes. Genetic variants in the CHIT1 andAMCase genes will be tested for association with skin test sensitivity to fungal aeroallergens and otherasthma phenotypes in a cohort of 1700 asthma cases provided by the Asthma Clinical Research Networkand independent cohorts of Latino and African American subjects.
Aim 2 will examine the autonomous andinteractive effects of genetic variants in 26 TGFp pathway genes on asthma and asthma-related phenotypesin several large, well-characterized, ethnically diverse asthma family based and case-control cohorts.Associated SNPs will be replicated in independent populations.
Aim 3 will evaluate the functionalsignificance of the genes and genetic variants examined in Aims 1 and 2. We will analyze the relative geneand protein expression of CHIT1 and AMCase in specific lung compartments and the effects of geneticvariants on expression of splice variants and levels of airway chitinase activity. We will determine if any ofthe 26 TGFp pathway genes analyzed show differential expression in the lung in asthma.
Our aims arefounded on preliminary data from human subjects and integrate closely with the scientific themes of projects1 and 2. Together, our studies will greatly advance understanding of the roles of chitinases and TGFp familymembers in allergy and asthma and could suggest novel treatment approaches.Lay summary: We will examine the effect of genetic variation in the CHIT1, AMCase and TGFp pathway onasthma and asthma related traits in ethnically diverse populations. We will also examine the effect of geneticvariation in these genes on gene and protein expression in the lungs of subjects with asthma.
Showing the most recent 10 out of 117 publications
