Improving Prematurity-related Respiratory Outcomes at Vanderbilt (IMPROV)

描述(申请人提供)：早产与支气管肺发育不良(BPD)有关，这是一种慢性肺部疾病，每年影响美国10,000多名婴儿的肺部和整体健康。该临床研究中心(CRC)的长期目标是将生化、遗传和生物信息学研究转化为创新的干预措施，以改善极有可能长期患肺部疾病的早产儿的结局。我们的建议特别关注尿素循环-一氧化氮(UC-NO)和谷胱甘肽(GSH)途径，它们是发育中的肺对宫外环境做出反应的关键和相互关联的机制。总体假设：(1)UC-NO和GSH通路中的生化不成熟和功能遗传变异调节BPD表型谱；(2)NO不足和自由基过剩的持续时间和程度预测BPD的严重程度，并与NICU出院后肺部并发症相关。为了验证我们的假设，我们的CRC将招募250名出生体重在510-1250克之间的婴儿，并跟踪观察幸存者一年的生活。我们的假说涉及未成熟的肝脏和肠道合成瓜氨酸和谷胱甘肽的能力、UC-NO和GSH途径的功能遗传变异、营养缺乏以及早产的生理和环境压力。由此产生的NO缺乏和自由基过剩改变了肺血管和肺泡的发育。我们的生物标记物发现概念包括：(A)收集血浆、尿液、红细胞、DNA和气管吸出物，以测量NO和GSH前体的充分性，NO代谢物和GSH的产生，这些途径中的功能性遗传变异，以及体内氧化应激的生物标记物，以及(B)验证这些生物标记物用于BPD患者的诊断和长期预后。一种使用机器学习和预测模型的生物信息学方法已经开发出来，用于36周和40周月经后以及出院后12个月的呼吸道表型和风险分层。这些目标的实现将促进新的临床试验设计，以测试预防BPD和改善早产儿长期肺健康的新疗法。(摘要结束) 相关性：在美国，每年有10,000多名早产儿患上支气管肺发育不良(BPD)，这是一种慢性肺部疾病，与长期和反复住院以及终身肺功能改变有关。这项提案将探索发育、遗传和环境的相互作用，并确定预测BPD发展和严重程度的生化标记物，最终目标是设计新的治疗方法来预防BPD并改善早产儿的长期肺功能。

DESCRIPTION (provided by applicant): Preterm birth is associated with bronchopulmonary dysplasia (BPD), a form of chronic lung disease that impacts the pulmonary and overall health of more than 10,000 infants in the US each year. The long-term objective of this Clinical Research Center (CRC) is translation of biochemical, genetic and bioinformatics research into innovative interventions that improve outcomes of extremely preterm infants at risk for long- term pulmonary morbidity. Our proposal focuses specifically on the urea cycle-nitric oxide (UC-NO) and glutathione (GSH) pathways as pivotal and interrelated mechanisms in the response of the developing lung to the extrauterine environment. Overall hypotheses: (1) Biochemical immaturity and functional genetic variation in the UC-NO and GSH pathways modulate the BPD phenotype spectrum; (2) The duration and degree of NO insufficiency and free radical excess predicts BPD severity and correlates with pulmonary morbidity after NICU discharge. To investigate our hypothesis, our CRC will enroll 250 infants with birthweights 510-1250 grams and follow the survivors through 1 year of life. Our hypothesis invokes an immature hepatic and gut synthetic capacity to make citrulline and GSH, functional genetic variations in the UC-NO and GSH pathways, nutritional deficiencies and the physiologic and environmental stress of preterm birth. The resultant NO deficiency and free radical excess alters pulmonary vascular and alveolar development. Our biomarker discovery concept includes (a) collection of plasma, urine, red blood cells, DNA and tracheal aspirates for measurements of NO and GSH precursor sufficiency, production of NO metabolites and GSH, functional genetic variants in these pathways, and biomarkers of in vivo oxidative stress and (b) validation of these biomarkers for diagnosis and long term prognosis of patients with BPD. A bioinformatics approach using machine learning and predictive modeling has been developed for respiratory phenotyping and risk stratification at 36 weeks and 40 weeks postmenstrual age and at 12 months after hospital discharge. Accomplishment of these goals will promote novel clinical trials design to test new therapies to prevent BPD and improve long term pulmonary health of infants born preterm. (End of Abstract) RELEVANCE: Each year in the US, more than 10,000 premature infants develop bronchopulmonary dysplasia (BPD), a chronic lung disease associated with prolonged and recurrent hospitalizations and lifelong alterations in lung function. This proposal will explore developmental, genetic and environmental interactions and identify biochemical markers to predict BPD development and severity, with the ultimate goal of designing new treatments to prevent BPD and improve long-term lung function in premature infants.