Asthma is characterized by allergic airway inflammation and airway remodeling which underlie the clinical characteristics of airflow limitation, bronchial hyperresponsiveness, and susceptibility to exacerbation. Important questions remain for how asthma develops, the mechanisms of allergen sensitization, and the factors that contribute to the persistence of asthmatic airway changes over a lifetime. Here we propose clinical studies to investigate fundamental questions about the role of chitinases and TGFp in initiating and perpetuating allergic asthma. We will combine comprehensive genetic studies with detailed translational studies to address hypotheses for how polymorphisms in chitinase and TGFp pathway genes influence allergen sensitization, asthma susceptibility and expression of asthma-related phenotypes. Aim 1 will determine the independent and dependent effects of genetic variants in chitinases (AMCase/CHIT1) on sensitization to fungal aeroallergens and other asthma outcomes. Genetic variants in the CHIT1 and AMCase genes will be tested for association with skin test sensitivity to fungal aeroallergens and other asthma phenotypes in a cohort of 1700 asthma cases provided by the Asthma Clinical Research Network and independent cohorts of Latino and African American subjects. Aim 2 will examine the autonomous and interactive effects of genetic variants in 26 TGFp pathway genes on asthma and asthma-related phenotypes in 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 functional significance of the genes and genetic variants examined in Aims 1 and 2. We will analyze the relative gene and protein expression of CHIT1 and AMCase in specific lung compartments and the effects of genetic variants on expression of splice variants and levels of airway chitinase activity. We will determine if any of the 26 TGFp pathway genes analyzed show differential expression in the lung in asthma. Our aims are founded on preliminary data from human subjects and integrate closely with the scientific themes of projects 1 and 2. Together, our studies will greatly advance understanding of the roles of chitinases and TGFp family members 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 on asthma and asthma related traits in ethnically diverse populations. We will also examine the effect of genetic variation in these genes on gene and protein expression in the lungs of subjects with asthma.