RETINOIC ACID REGULATION OF LUNG DEVELOPMENT

Boston University Medical Campus, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The goal of this project is to investigate how retinoic acid (RA), the active form of vitamin-A, influences the development of airways in the embryo and how disruption of this mechanism may lead to airway hyperresponsiveness during postnatal life. Here we propose to characterize the role of RA in the development of the airway smooth muscle (ASM) as it relates to airway physiology in the adult lung and in an asthma model. We have preliminary evidence that during lung development RA regulates expression of smooth muscle genes influencing whether the muscle progenitor will acquire a contractile or synthetic phenotype. Our data suggest that pre-natal RA deficiency may foster the development of a contractile phenotype in airways. Furthermore we found that the upregulation of contractile genes in RA deficiency is accompanied by significant changes in expression of chromatin remodeling and DNA methylation genes, suggesting that RA may regulate the SM phenotype through epigenetic mechanisms. Here we hypothesize that endogenous RA serves to maintain ASM cells in a less differentiated state to allow proper SM remodeling as the airways form. To address this issue we propose to: Aim 1: Investigate how prenatal RA deficiency influences the airway smooth muscle phenotype, contractile properties and responsiveness to contractile agonists in developing airways; Aim 2: Study the effect of prenatal RA deficiency in the development of airway hyperactivity during postnatal life, using a genetic model to induce dietary Vitamin A-deficiency restricted to prenatal life, and an asthma murine model. Aim 3: Characterize the role for epigenetic mechanisms in the RA control of ASM gene expression.