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

糖皮质激素、视黄醇和 cAMP 信号在肺发育和新生儿呼吸功能障碍中的作用

• 批准号: nhmrc : 299888
• 负责人: A/Pr Timothy Cole
• 金额: $ 29.81万
• 依托单位: Monash University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-glucocorticoids-retinol-respiratory-dysfunction/95299
• 关键词: role; glucocorticoids; retinol; cAMP; signaling

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

出生时肺部发育不全和成年后肺部疾病（如肺气肿、急性呼吸窘迫和哮喘）是住院和死亡的主要原因。世界卫生组织将呼吸系统疾病排在全球疾病负担的第6位。早产伴有相关的呼吸系统并发症约占所有人类出生的10%，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在降低RDS发生率方面具有重要益处，从而降低新生儿死亡率。糖皮质激素促进肺成熟，但其确切的详细作用尚不完全清楚。其他全身激素和因子，如维生素A（维甲酸的前体）在调节、完成和维持肺的正常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，被认为是慢性肺部疾病的一个原因，如支气管肺发育不良，这对婴儿来说经常是一个问题。详细了解这些激素如何在肺中起作用，对于未来改善出生时呼吸窘迫和成年后其他呼吸系统疾病（肺气肿、哮喘）的治疗至关重要。我们已经开发了许多小鼠模型来研究这些激素如何在肺部起作用，并使我们能够进行在人体系统中不可能进行的研究。利用这些糖皮质激素、视黄酸（维生素A）和cAMP信号的激素抗性小鼠模型，我们将详细研究这些激素在发育中的肺部如何起作用。结果将是详细的知识和作用机制，这对于设计和测试针对出生时未成熟肺和成人肺功能障碍和疾病的新药和疗法至关重要