Improving Prematurity-related Respiratory Outcomes at Vanderbilt (IMPROV)

改善范德比尔特与早产相关的呼吸结果 (IMPROV)

• 批准号: 8675906
• 负责人: Judy Lynn Aschner
• 金额: $ 33.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675906
• 关键词: Admission activity; Age; Alveolar; Amino Acids; Arginine; Aspirate substance; Beds; Biochemical; Biochemical Genetics; Biochemical Markers; Bioinformatics; Biological Markers; Blood; Blood Vessels; Bronchopulmonary Dysplasia; Categories; Censuses; Chronic lung disease; Citrulline; Clinical; Clinical Data; Clinical Research; Clinical Trials Design; Collection; County Hospitals; Cysteine; DNA; DNA Repository; Data; Data Collection; Data Set; Development; Diagnosis; Enrollment; Environment; Erythrocytes; F2-Isoprostanes; Free Radicals; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Glutathione; Glutathione Disulfide; Goals; Health; Hepatic; Homocysteine; Homocystine; Hospitalization; Hospitals; Infant; Infant Health; Intervention; Isoprostanes; Libraries; Life; Lung; Lung diseases; Machine Learning; Malnutrition; Measurement; Measures; Methionine; Modeling; Morbidity - disease rate; Nitric Oxide; Nutritional; Online Systems; Ornithine; Outcome; Oxidative Stress; Oxides; Pathogenesis; Pathway interactions; Patients; Pediatric Hospitals; Phenotype; Physiological; Plasma; Predictive Value; Premature Birth; Premature Infant; Principal Investigator; Production; Recruitment Activity; Recurrence; Research; Research Project Grants; Respiratory physiology; Risk; Sampling; Secure; Severities; Specific qualifier value; Specimen; Stratification; Stress; Study Subject; Survivors; System; Testing; Time; Translations; Urine; Validation; Variant; abstracting; base; biobank; cohort; design; developmental genetics; gastrointestinal; genetic variant; improved; in vivo; innovation; novel; open source; outcome forecast; oxidant stress; predictive modeling; premature; prevent; respiratory; response; sample collection; urea cycle

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.

描述（由申请人提供）：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干预措施，以改善面临长期肺部疾病风险的极度早产儿的结局。我们的提案特别关注尿素循环一氧化氮（UC-NO）和谷胱甘肽（GSH）途径，作为发育中的肺对子宫外环境的反应的关键和相互关联的机制。总体假设：（1）UC-NO和GSH通路的生化不成熟和功能性遗传变异调节BPD表型谱； (2) NO 不足和自由基过量的持续时间和程度可预测 BPD 的严重程度，并与 NICU 出院后的肺部发病率相关。为了验证我们的假设，我们的 CRC 将招募 250 名出生体重为 510-1250 克的婴儿，并对幸存者进行为期 1 年的跟踪调查。我们的假设涉及未成熟的肝脏和肠道合成瓜氨酸和 GSH 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。由此产生的一氧化氮缺乏和自由基过量会改变肺血管和肺泡的发育。我们的生物标志物发现概念包括 (a) 收集血浆、尿液、红细胞、DNA 和气管抽吸物，用于测量 NO 和 GSH 前体充足性、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志物，以及 (b) 验证这些生物标志物用于 BPD 患者的诊断和长期预后。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，用于月经后 36 周和 40 周以及出院后 12 个月的呼吸表型和风险分层。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部健康的新疗法。 （摘要完） 相关性：在美国，每年有超过 10,000 名早产儿患上支气管肺发育不良 (BPD)，这是一种与长期和反复住院以及肺功能终生改变相关的慢性肺部疾病。该提案将探索发育、遗传和环境的相互作用，并确定生化标记物来预测 BPD 的发展和严重程度，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。