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）有关，这是每年美国10,000多名婴儿的肺部和整体健康状况的一种形式。该临床研究中心（CRC）的长期目标是将生物化学，遗传和生物信息学研究转化为创新干预措施，这些干预措施改善了长期肺部发育率有风险的极早婴儿的预后。我们的建议专门针对尿素周期氧化氧化物（UC-NO）和谷胱甘肽（GSH）途径，作为在发育中的肺对额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途径中的生化不成熟和功能性遗传变异调节BPD表型光谱； （2）无需不足和自由基多余的持续时间和程度预测了BPD的严重程度，并且与NICU排出后的肺发病率相关。为了调查我们的假设，我们的CRC将招募250名患有510-1250克出生体重的婴儿，并在1年的生命中跟随幸存者。我们的假设引起了不成熟的肝和肠道合成能力，使瓜氨酸和GSH，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。最终没有缺乏和自由基过多会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）等离子体，尿液，红细胞，DNA和气管质量的质量，以测量NO和GSH前体的足够，产生NO代谢物和GSH，在这些途径中的功能遗传变异，以及在这些生物氧化应激和（B）诊断诊断的患者氧化应激和（B）验证的生物标志物中的生物标志物。使用机器学习和预测建模的生物信息学方法已开发用于在月经后36周零40周的呼吸表型和风险分层，并在出院后12个月后进行。实现这些目标将促进新颖的临床试验设计，以测试新疗法，以防止BPD并改善婴儿早产的婴儿长期肺部健康。 （抽象的结尾） 相关性：在美国，每年，有10,000多名早产儿就会出现支气管肺发育不良（BPD），这是一种慢性肺部疾病，与长期和复发性住院和肺功能的终生改变有关。该提案将探索发展，遗传和环境相互作用，并确定生化标记以预测BPD的发展和严重性，其最终目标是设计新的治疗方法以防止BPD并改善早产儿的长期肺功能。