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: 8468005
• 负责人: Judy Lynn Aschner
• 金额: $ 51.98万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468005
• 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）相关，BPD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）的长期目标是将生物化学、遗传学和生物信息学研究转化为创新干预措施，以改善存在长期肺部发病风险的极早产儿的结局。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）途径作为发育中的肺对子宫外环境的反应中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不足和自由基过量的持续时间和程度预测BPD严重程度，并与NICU出院后的肺部发病率相关。为了研究我们的假设，我们的CRC将招募250名出生体重为510-1250克的婴儿，并随访幸存者1年。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途径的功能性遗传变异、营养缺乏以及早产的生理和环境压力。由此产生的NO缺乏和自由基过量改变肺血管和肺泡发育。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前体的充足性、NO代谢物和GSH的产生、这些途径中的功能性遗传变体和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诊断和BPD患者的长期预后。使用机器学习和预测建模的生物信息学方法已被开发用于月经后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。(End摘要） 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病。该提案将探索发育、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志物，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。