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.
Studies strongly suggest that susceptibility for asthma may develop from early exposures in utero to environmental agents or nutritional changes, and that asthma severity is associated with low Vitamin A levels in children. Here we will investigate how prenatal deficiency in vitamin A influences development of the airway- associated muscle layer and how this predisposes to increased airway reactivity to spasmogenic drugs and asthmatic stimuli in adult life.
|Marquez, Hector A; Cardoso, Wellington V (2016) Vitamin A-retinoid signaling in pulmonary development and disease. Mol Cell Pediatr 3:28|
|Mahoney, John E; Mori, Munemasa; Szymaniak, Aleksander D et al. (2014) The hippo pathway effector Yap controls patterning and differentiation of airway epithelial progenitors. Dev Cell 30:137-50|
|Chen, Felicia; Marquez, Hector; Kim, Youn-Kyung et al. (2014) Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice. J Clin Invest 124:801-11|
|Hamvas, Aaron; Deterding, Robin; Balch, William E et al. (2014) Diffuse lung disease in children: summary of a scientific conference. Pediatr Pulmonol 49:400-9|
|Morrisey, Edward E; Cardoso, Wellington V; Lane, Robert H et al. (2013) Molecular determinants of lung development. Ann Am Thorac Soc 10:S12-6|
|Manoli, Sara E; Smith, Lacey A; Vyhlidal, Carrie A et al. (2012) Maternal smoking and the retinoid pathway in the developing lung. Respir Res 13:42|
|Chen, Felicia; Cao, Yuxia; Qian, Jun et al. (2010) A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium. J Clin Invest 120:2040-8|
|Ballas, Samir K; Bauserman, Robert L; McCarthy, William F et al. (2010) Hydroxyurea and acute painful crises in sickle cell anemia: effects on hospital length of stay and opioid utilization during hospitalization, outpatient acute care contacts, and at home. J Pain Symptom Manage 40:870-82|
|Shi, Wei; Chen, Felicia; Cardoso, Wellington V (2009) Mechanisms of lung development: contribution to adult lung disease and relevance to chronic obstructive pulmonary disease. Proc Am Thorac Soc 6:558-63|
|Cardoso, Wellington V; Whitsett, Jeffrey A (2008) Resident cellular components of the lung: developmental aspects. Proc Am Thorac Soc 5:767-71|
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