Metabolic mechanisms induced by enteral DHA and ARA supplementation in preterm infants

肠内补充 DHA 和 ARA 诱导早产儿的代谢机制

• 批准号: 10650333
• 负责人: CAMILIA R MARTIN
• 金额: $ 71.29万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650333
• 关键词: Acceleration; Address; Age; Arachidonic Acids; Bioinformatics; Biological; Biological Markers; Biological Process; Biology; Biometry; Birth; Brain; Bronchopulmonary Dysplasia; Clinical; Critical Illness; Data; Derivation procedure; Development; Diet; Docosahexaenoic Acids; Docosahexaenoic acid supplementation; Dose; Enteral; Evidence based practice; Extremely low gestational age newborn; Eye Development; Failure; Fatty Acids; Fatty Change; Fetal Development; Future; Genes; Growth; Health; Health Benefit; Incidence; Infant; Inflammatory; Intravenous; Lipids; Lung diseases; Mediator; Metabolic; Metabolic Pathway; Metabolism; Molecular; National Institute of Child Health and Human Development; Neonatal; Neonatal Intensive Care Units; Neonatology; Neurocognitive; Nutrient; Nutritional; Nutritional Study; Nutritional status; Organ; Outcome; Pathway interactions; Polyunsaturated Fatty Acids; Population; Pregnancy; Premature Birth; Premature Infant; Prevention; Printing; Production; Public Health; Recommendation; Reporting; Research; Role; Specificity; Steroids; Strategic Planning; Supplementation; System; Translating; United States National Institutes of Health; Vulnerable Populations; animal data; circulating biomarkers; clinical translation; efficacy clinical trial; evidence base; extreme prematurity; fatty acid metabolism; fatty acid supplementation; fetal; human data; inflammatory marker; interest; lipid metabolism; lipidomics; long chain fatty acid; lung injury; metabolic abnormality assessment; multidisciplinary; nutrition; nutrition related genetics; nutritional genomics; organ growth; perinatal medicine; pleiotropism; postnatal; postnatal period; pre-clinical; prevent; randomized, clinical trials; response

Preterm birth indicates an end to the rich fetal supply of polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and Arachidonic Acid (ARA) which are a critical building blocks for brain and eye development and an important inflammatory modulator. Yet, for almost 40 years, enteral supplementation of DHA and ARA to replace lost fetal accretion has failed to translate into long-standing clinical benefit. The failure to understand the metabolism and induced molecular changes of fatty acid supplementation during the postnatal period has led to erroneous assumptions and replacement strategies that are, at best, not clinical beneficial and, at worst, harmful. The overall study objective of this proposal is to investigate the induced metabolism and downstream molecular mechanisms of enteral DHA and ARA supplementation from birth to 36 weeks' postnatal age in the extremely preterm infant. We have assembled a multidisciplinary team with expertise in neonatal-perinatal medicine and biostatistics/bioinformatics. The team of neonatologists are clinical and research leaders in nutrition, growth, and fatty acids and represents five level III/IV neonatal intensive care units with diverse demographic populations. We hypothesize that metabolism of DHA and ARA enteral supplementation is developmentally regulated and the impact of lipid derived metabolites on biology is dependent on the health state of the infant (context specificity). To interrogate our hypothesis, we propose a multi-center, randomized clinical trial to evaluate lipidomic actions of combined DHA and ARA supplementation from birth to 36 weeks postmenstrual age in 280 extremely low gestational age newborns born between 25 0/7 and 29 6/7 weeks of gestation. The following aims will be evaluated: Aim 1 – Identify the impact of combined enteral DHA and ARA supplementation on fatty acid metabolism including derivation of specialized pro-resolving mediators (SPMs) and oxylipin production and, Aim 2 – Determine the multisystemic change in circulating markers of inflammation and organ development and integrity as a function of enteral DHA/ARA supplementation. Successful completion of these aims will define developmentally regulated fatty acid metabolism in the immature host and impact of fatty acid supplementation on critical biological functions. Mechanistic data is required to bridge the scientific gap to appropriate clinical translation that is effective and safe. These data will inform a biologically rational approach to fatty acid delivery in preterm infants and identify molecular read-outs that may serve as biomarkers in future trials of clinical efficacy.

早产意味着胎儿的多不饱和脂肪酸供应的结束，如二十二碳六烯酸（DHA）和花生四烯酸（ARA），这些脂肪酸是大脑和眼睛发育的重要组成部分，也是重要的炎症调节剂。然而，近40年来，肠内补充DHA和ARA来替代胎儿增重的方法未能转化为长期的临床效益。对产后脂肪酸补充的代谢和诱导的分子变化的不了解导致了错误的假设和替代策略，这些假设和替代策略在最好的情况下是没有临床益处的，在最坏的情况下是有害的。本研究的总体目的是研究出生后至出生后36周龄的极早产儿肠内补充DHA和ARA诱导代谢及其下游分子机制。我们已经组建了一个多学科团队，具有新生儿-围产期医学和生物统计学/生物信息学方面的专业知识。新生儿科医生团队是营养、生长和脂肪酸方面的临床和研究领导者，代表着5个具有不同人口结构的III/IV级新生儿重症监护病房。我们假设DHA和ARA肠内补充的代谢受到发育调节，脂质衍生代谢物对生物学的影响取决于婴儿的健康状况（上下文特异性）。为了验证我们的假设，我们提出了一项多中心随机临床试验，以评估280名出生在妊娠25 0/7周至29 6/7周之间的极低胎龄新生儿从出生到经后36周联合补充DHA和ARA的脂质组学作用。以下目标将被评估：目标1 -确定联合肠内DHA和ARA补充对脂肪酸代谢的影响，包括特殊促溶解介质（SPMs）的衍生和氧化脂质的产生；目标2 -确定肠内DHA/ARA补充对炎症和器官发育和完整性循环标志物的多系统变化的作用。这些目标的成功完成将确定未成熟宿主中发育调节的脂肪酸代谢以及脂肪酸补充对关键生物学功能的影响。需要机械数据来弥合科学差距，以适当的临床翻译是有效和安全的。这些数据将为早产儿脂肪酸输送提供一种生物学上合理的方法，并确定可能在未来临床疗效试验中作为生物标志物的分子读数。