Neural Pathogenesis of Airway Smooth Muscle Defects in Airway Disease

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DESCRIPTION (provided by applicant): Exaggerated airway smooth muscle (ASM) contraction and airway narrowing are hallmark traits of asthma. Contraction of ASM is predominantly regulated by the nervous system. In airway diseases such as asthma, inflammation causes neural regulation of ASM to become defective, thus promoting hypercontraction. We recently generated a novel porcine model of a chronic airway disease (cystic fibrosis, CF), and discovered that newborn CF pigs display hypercontracted ASM in the absence of airway infection and inflammation. Thus, the mechanism of ASM hypercontraction in CF remains unknown. In the current application, the candidate hypothesizes that defective neural regulation of ASM causes hypercontraction independent of airway inflammation. She hypothesizes this based upon her work indicating that there are several novel nervous system phenotypes in newborn pigs with CF. These include reduced axon density, decreased innervation of the airway, and decreased nerve function. The candidate proposes to: 1) determine whether inhibitory neural control (pro-relaxation) of ASM is defective in CF pigs; and 2) investigate whether blocking pro-contractile neural input ameliorates ASM hypercontraction in CF pigs. The candidate's long-term career goal is to become a recognized leader in neuroscience and airway disease research. She plans to advance both fields by examining neural regulation of ASM using porcine models. The selection of the porcine model is particularly relevant because the airway anatomy and physiology, as well as the nervous system, more closely resemble humans than traditional rodent models. In the current K99/R00 application, the candidate will gain intellectual, professional and technical skills that will allo her to become an independent and successful investigator specializing in neural regulation of ASM. During the mentored phase, she will learn ASM biology, lung slice culturing, Ca2+ imaging, morphometry, and whole animal pulmonary mechanics using flexiVent. She has created an exceptional mentoring team and training plan to ensure she learns these skills. In addition, the candidate will give formal presentations at Mayo Clinic, attend the American Asthma Foundation Funding Breakthrough Research Annual Meeting of Awardees, review manuscripts for American Journal of Respiratory Cell, serve as a group leader for a medical students "Problem-Based Learning" course, and attain skills important for managing budgets. The candidate will utilize these skills during her independent phase to investigate neural regulation of ASM in acid-induced airway injury. This topic is highly significant as acidification f the airway occurs in asthma and acidic pH potently activates axons innervating the airway. Hence, the candidate has an unprecedented opportunity to elucidate neural mechanisms involved in ASM hypercontraction using models with direct relevance to human disease. In summary, this award will train the candidate to become a leader in neuroscience and airway disease research, thereby advancing the field and enhancing the lives of people living with airway disease.