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

出生时肺部发育不全和成人肺部疾病(如肺气肿、急性呼吸窘迫和哮喘)是住院和死亡的主要原因。世界卫生组织将顽固性疾病列为全球疾病负担的第六位。早产与相关的呼吸道并发症发生在所有人类出生的10%左右，占与先天性异常无关的新生儿死亡的75%。呼吸窘迫综合征(RDS)是早产的主要并发症，常规的产前糖皮质激素治疗对减少RDS的发生率、降低新生儿死亡率具有重要意义。糖皮质激素可促进肺成熟，但其确切的详细作用尚不完全清楚。其他系统激素和因子，如维生素A(维甲酸前体)，在调节、完成和维持正常的肺发育和功能方面也很重要。维生素A缺乏会改变肺的结构和功能，被认为是导致慢性肺部疾病的一个因素，如支气管肺发育不良，这些疾病通常会给婴儿带来问题。详细了解这些激素如何在肺部发挥作用，对于未来改进出生时呼吸窘迫和成年期间其他呼吸系统疾病(肺气肿、哮喘)的治疗至关重要。我们已经开发了一些小鼠模型来研究这些激素如何在肺部发挥作用，并允许我们进行在人类系统中不可能进行的研究。利用这些激素抵抗糖皮质激素、维甲酸(维生素A)和cAMP信号的小鼠模型，我们将详细研究这些激素如何在发育中的肺中发挥作用。结果将是详细的知识和作用机制，这些知识和作用机制对于设计和测试新的药物和治疗出生时未成熟的肺以及成人肺功能障碍和疾病至关重要。

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