Placental Proteins and Prematurity

胎盘蛋白与早产

• 批准号: 10493397
• 负责人: Thomas Jansson
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493397
• 关键词: 37 weeks gestation; 5 year old; Affect; Animal Model; Animals; Binding Proteins; Birth; Blindness; Blood; Blood Circulation; Brain; Bronchopulmonary Dysplasia; Cardiac development; Cardiovascular system; Caring; Cause of Death; Cavia; Cerebral Palsy; Child; Chronic lung disease; Development; Fetal Development; Fetal Tissues; Fetus; Forebrain Development; Growth; Health; Hour; Human; Impaired cognition; Infant; Intellectual functioning disability; Intervention; Intestines; Lead; Life; Link; Lung; Mass Spectrum Analysis; Mediating; Mus; Necrotizing Enterocolitis; Neonatal; Neonatal Intensive Care Units; Newborn Infant; Nutritional Support; Outcome; Physiology; Placenta; Plasma; Pregnancy; Pregnancy Proteins; Premature Birth; Premature Infant; Premature Labor; Process; Progesterone; Proteins; Proteome; Proteomics; Public Health; Pump; Quality of Care; Reporting; Retina; Retinal Diseases; Risk; Sampling; Serotonin; Structure of umbilical artery; Supplementation; Technology; Testing; Thinking; Umbilical vein; United States; Venous; Western Blotting; Work; angiogenesis; aptamer; base; biobank; body system; fetal; guinea pig model; hearing impairment; high reward; high risk; improved; improved functioning; improved outcome; innovation; intrauterine environment; intraventricular hemorrhage; long-term sequelae; lung development; neonatal morbidity; neurogenesis; novel; nutrition; obstetrical complication; organ growth; postnatal; premature; prevent; pup; respiratory; subcutaneous

Each year, 12-18 million infants worldwide, representing ~10% of all births, are born preterm (before 37 weeks of gestation). The mechanisms underpinning preterm birth are poorly understood and, with the possible exception of progesterone, no interventions are currently available to prevent preterm labor. The management of the preterm infant has improved over the last 30 years, however despite this progress, prematurity remains the second most common direct cause of death among children under 5 years of age. In addition, infants born preterm are at risk of neonatal morbidity (e.g., intraventricular hemorrhage, bronchopulmonary dysplasia and necrotizing enterocolitis) and long-term sequelae including chronic lung disease, retinopathy, cognitive impairment and poor neurodevelopmental outcomes. Emerging evidence show that factors secreted by the placenta are critical for normal fetal organ development. One of the most fundamental differences between fetal and postnatal life is the instantaneous discontinuation of the umbilical circulation at delivery, depriving the premature infant of placental factors, such as proteins, critical for fetal organ development. However, the identity of proteins secreted by the human placenta into the fetal circulation remain largely unknown. Using the SOMALOGIC proteomic platform, we recently reported that 341 proteins are secreted by the human term placenta into the fetal circulation. Remarkably, a large number of these proteins could be linked to processes such as angiogenesis and neurogenesis, suggesting that a subset of these proteins are critical for the normal development of fetal tissues such as the brain, lung, and cardiovascular system. However, it is currently unknown if these or other proteins are secreted by the placenta into the fetal circulation earlier in gestation and if supplementation of a subset of these proteins could improve outcomes in prematurity. In this high risk/high reward proposal we will test the central hypothesis that proteins associated with the development of the brain, lung, retina, intestine and cardiovascular system are secreted by the placenta into the fetal circulation in extremely and very preterm infants and administration of a subset of these proteins improve outcomes in a guinea-pig model of prematurity. Our approach will be to determine the abundance of ~5000 proteins in umbilical artery and vein and neonatal blood of extremely and very preterm infants, using a novel Slow Off-rate Modified Aptamer (SOMA) proteomics platform, allowing us to characterize the preterm infant plasma proteome in unprecedented depth. We will test the ability of a small subset of these proteins to improve outcomes using a unique premature guinea-pig model. This proposal represents a shift in the paradigm how to approach the problem of prematurity by focusing on the intrauterine environment that the infant born preterm has been separated prematurely from, rather than optimizing the quality of care based on postnatal physiology and nutrition in the premature infant. The proposed work is highly significant because it has the potential to lead to the development of fundamentally novel intervention strategies to improve outcomes in premature infants.

全世界每年有 12-1800 万婴儿早产（37 周之前），约占所有新生儿的 10% 妊娠期）。人们对早产的机制知之甚少，并且可能 除黄体酮外，目前没有任何干预措施可以预防早产。管理层 过去 30 年来，早产儿的发病率有所改善，但尽管取得了这些进展，早产问题仍然存在 5 岁以下儿童第二常见的直接死亡原因。此外，出生的婴儿 早产儿有新生儿发病的风险（例如，脑室内出血、支气管肺发育不良和 坏死性小肠结肠炎）和长期后遗症，包括慢性肺病、视网膜病变、认知障碍 损伤和神经发育结果不佳。新出现的证据表明，由 胎盘对于胎儿器官的正常发育至关重要。之间最根本的区别之一 胎儿和产后生命是指分娩时脐带循环立即停止，剥夺了胎儿的生命。 早产儿的胎盘因子，例如对胎儿器官发育至关重要的蛋白质。然而， 人类胎盘分泌到胎儿循环中的蛋白质的身份仍然很大程度上未知。使用 SOMALOGIC蛋白质组平台，我们最近报道了人类分泌的341种蛋白质 胎盘进入胎儿循环。值得注意的是，大量这些蛋白质可能与过程相关 例如血管生成和神经发生，表明这些蛋白质的一个子集对于正常的生命活动至关重要 胎儿组织的发育，如大脑、肺和心血管系统。然而，目前 未知这些或其他蛋白质是否在妊娠早期由胎盘分泌到胎儿循环中 补充这些蛋白质的一部分是否可以改善早产儿的结局。在这个高风险/高 奖励提案我们将测试与大脑发育相关的蛋白质的中心假设， 肺、视网膜、肠道和心血管系统由胎盘分泌进入胎儿循环 极早产儿和极早产儿以及这些蛋白质的子集的施用可改善结果 早产豚鼠模型。我们的方法是确定约 5000 种蛋白质的丰度 使用新型慢解离率对极早产儿和极早产儿的脐动脉和静脉以及新生儿血液进行分析 改良适体 (SOMA) 蛋白质组学平台，使我们能够表征早产儿血浆 蛋白质组的深度前所未有。我们将测试这些蛋白质的一小部分改善的能力 使用独特的早产豚鼠模型得出的结果。该提案代表了范式的转变，如何 通过关注早产儿出生的宫内环境来解决早产问题 过早地与产后生理学分离，而不是优化基于产后生理学的护理质量 和早产儿的营养。拟议的工作非常重要，因为它有潜力 导致开发根本性新颖的干预策略，以改善早产儿的结果 婴儿。