Project Summary Asthma currently affects over 300 million individuals worldwide and the prevalence is continually increasing. Approximately 10% of asthmatics have uncontrolled or poorly controlled symptoms and it is this population that urgently need improved targeted therapies and management strategies in order to reduce the high morbidity and socio-economic burden, estimated to be 14.7 billion dollars annually in the United States alone. The exact mechanisms behind the pathophysiology of asthma remain uncertain. Airway smooth muscle (ASM) is known to play a critical and multifaceted role, yet our knowledge on the role of ASM in asthma is limited due to an inability to directly visualize and study the 3D structure of ASM, and the relationship to functional bronchoconstriction in patients. The real-time evaluation of ASM is critical in furthering our understanding of the pathophysiology of asthma, for classifying asthma phenotypes, for tailoring treatment, and for assessing and monitoring the response to therapy. In this award we will develop a custom optical imaging platform based on polarization-sensitive optical coherence tomography (PS-OCT) that will enable the accurate quantification of ASM hyperplasia and hypertrophy, epithelial disruption and hypertrophy, subepithelial fibrosis, mucosal thickness increases, mucus metaplasia, in vivo. We will develop and validate novel dual-layer calibrating catheters that will enable accurate assessment of tissue fiber orientation and birefringence signal intensity. We will additionally develop and validate automated calibration and processing software that will provide real-time visualization of ASM in vivo. These technological advancements will enable us to begin to answer important questions linking remodeling changes in airway wall structure with physiologic function. We will conduct a preclinical study in a sheep model of allergic asthma to test our hypothesis that remodeling plays both a protective and provocative role in bronchoconstriction, and that the presence of inflammation greatly increases bronchoconstriction. We will further translate this technology into the clinical setting in a multicenter clinical trial aimed at using our PS-OCT imaging system to phenotype asthma and to predict the response to bronchial thermoplasty. The unprecedented ability to study both the 3D structure of airway smooth muscle (ASM) and it’s function in vivo is likely to transform the study of asthma in patients in phenotyping populations, for therapy guidance, and in research endeavors aimed at studying the true role of ASM in asthma.