DESCRIPTION (provided by applicant): Asthma is characterized by airflow limitation and airway hyperresponsiveness (AHR). Airway smooth muscle (ASM), the primary effector of airway tone and responsiveness to constricting stimuli, therefore, is important to the pathogenesis of asthma. Experimental data and mathematical models indicate that ASM plays a central role in the pathogenesis of asthma by undergoing marked phenotypic changes, including the acquisition of a hypercontractile and hyperresponsive state. However, the precise molecular signals governing these changes in vivo is incompletely understood. We now have evidence that inhibition of retinoic acid (RA), the active metabolite of vitamin A, in adult mice for only fve days results in a significant increase in AHR and ASM mass without evidence of airway inflammation. Based on our preliminary findings and the emerging literature linking vitamin A to the maintenance of airway health in humans, we hypothesize that ongoing RA signaling in the adult airway is required to maintain normal airway health by regulating ASM phenotype. To test our hypothesis, we will identify the changes in airway structure and function in the setting of RA deficiency by using histologic, biochemical, and physiologic assays in live animals, freshly-isolated lungs, and precision-cut lung slices. We will establish whether RA signaling in ASM is mediated through its receptor RARβ in vivo. In addition, we will examine the influences of RA on the physical and molecular properties of ASM using freshly isolated mouse ASMs and human ASMs collected from donor lungs. Finally, we will investigate the regulation of TGFβ signaling in ASM by RA in vivo. At the end of this project, we will establish a functional link between vitamin A and airway homeostasis, deepen our understanding of the cellular, physical, and molecular features of ASM, and provide novel information on genes and pathways in the pathogenesis of diseases characterized by airflow obstruction.

PUBLIC HEALTH RELEVANCE: Asthma is characterized by excessive airway narrowing leading to shortness of breath. It is a tremendous public health burden, affecting more than 300 million people worldwide. The objective of this proposal is to study the consequences of short-term vitamin A deficiency on the phenotype of the airway smooth muscle, the tissue responsible for airway constriction.