The role of glucocorticoids, retinol and cAMP signaling in lung development and neonatal respiratory dysfunction

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Underdeveloped lungs at birth and adult lung diseases (ie emphysema, acute resipratory distress, and asthma) are a major cause of hopitalization and death. The World Health Organization ranks resipratory diseases at number 6 in the global burden of disease. Preterm birth with associated respiratory complications occurs in about 10% of all human births and accounts for 75% of neonatal deaths not associated with congenital abnormalities . Respiratory Distress Syndrome (RDS) is a major complication in preterm births and the routine antenatal treatment of glucocorticoids has a major benefit in reducing incidence of RDS leading to decreased neonatal mortality. Glucocorticoids improve lung maturation yet their exact detailed role is not fully understood. Other systemic hormones and factors , such as vitamin A (precursor for retinoic acid) are also important in regulating, completing and maintaining proper lung development and function. Vitamin A deficiency alters lung structure and function, and is believed to be a causal factor in chronic lung diseases such as bronchopulmonary dysplasia, frequently problematic to infants. Detailed understanding of how these hormones work in the lung is critical to the future improvement of treatments for respiratory distress at birth and other respiratory conditions (emphysema, asthma) during adult life. We have developed a number of mouse models to study how these hormones work in the lung and allows us to perform investigations not possible in the human system. Using these mouse models of hormone resistance for glucocorticoids, retinoic acid (vitamin A) and cAMP signaling we will study in detail how these hormones work in the developing lung. Outcomes will be detailed knowledge and mechanisms of action that are critical for the design and testing of novel agents and therapies for immature lungs at birth and in adult lung dysfunction and disease