Our broad goal is to investigate how retinoic acid (RA), the active form of vitamin A, influences the development of airway smooth muscle (SM) in the prenatal state and its effects in adult life. Maternal vitamin A deficiency has been shown to have deleterious impact in postnatal lung function in children. Vitamin A has been associated with airway hyper-reactivity and low levels have been associated with children with persistent asthma. The mechanisms that control growth and differentiation of airway SM in developing and adult lung are not well understood. RA is a well-known regulator of cellular activities in adult vascular and visceral smooth muscle and plays a vital role in lung development. Our initial studies show SM genes associated with a contractile phenotype were upregulated in RA-deficient foreguts while synthetic phenotype genes were upregulated in RA-sufficient cultures. Embryonic lung from control and a genetic RA deficient model showed similar pattern in gene expression. RA was also shown to induce expression of genes associated with epigenetic modifications. Subsequent analysis pointed to Jarid2 and Dnmt3b as epigeneitc candidates which RA likely targets to mediate the RA effects on SM phenotype. The induction of these candidate genes were also confirmed in lung specific mesenchymal cell lines. This induction of epigenetic regulators was accompanied by downregulation of genes associated with the contractile phenotype. This suggests airway SM phenotype and development are regulated by epigenetic changes which are influenced by RA. Here, we aim to determine the mechanism by which RA regulates airway SM differentiation via epigenetic controls. To this end, we will address the following aims: 1) Characterize DNA methylation status of SM gene expression influenced by RA during differentiation of lung mesenchymal cells; 2) Characterize histone modifications and binding of chromatin remodeling complexes in SM gene regulated by RA.
These aims will be accomplished by using both mesenchymal cell line and embryonic lung cultures to investigate the proposed RA-related changes in airway SM gene expression and epigenetic mechanisms associated with their regulation. These studies will benefit from the expertise, mentorship, and cutting edge research environment provided and fostered by The Pulmonary Center at Boston University School of Medicine who has offered a long standing and successful platform for training young investigators. Results from this proposed research plan will provide a new insight into the regulation of the SM differentiation program that may be critical in the pathogenesis of airway hyper-reactivity. These findings may then reveal new approaches in treatment and prevention of disease such as asthma.
There has been increasing evidence linking low levels of vitamin A with airway hyper-reactivity and persistent asthma in children. Little is known about the mechanism that regulates development of airway smooth muscle - the cause of airway hyper-reactivity. By understanding the regulation of airway smooth muscle during development and their effects during adult life; potential mechanisms for novel treatment and prevention of diseases like asthma can be developed.