Placental Proteins and Prematurity

每年，全世界有1200 - 1800万婴儿早产（37周之前），占所有出生婴儿的10 妊娠）。对早产的机制知之甚少， 除了黄体酮外，目前还没有预防早产的干预措施。管理 在过去的30年里，早产儿的出生率有所改善，然而，尽管取得了这些进展，早产仍然存在。 是5岁以下儿童死亡的第二大最常见直接原因。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、认知功能障碍、 损伤和不良的神经发育结果。新出现的证据表明， 胎盘对胎儿器官的正常发育至关重要。一个最根本的区别是 胎儿和产后生命是指分娩时脐带循环的瞬间中断， 早产儿胎盘因素，如蛋白质，对胎儿器官发育至关重要。但 由人胎盘分泌到胎儿循环中的蛋白质的特性仍然是未知的。使用 SOMALOGIC蛋白质组学平台，我们最近报道了341种蛋白质是由人类分泌的。 胎盘进入胎儿循环。值得注意的是，大量的这些蛋白质可能与过程有关， 如血管生成和神经发生，这表明这些蛋白质的一个子集对正常的 胎儿组织如脑、肺和心血管系统的发育。但目前 尚不清楚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， 如果补充这些蛋白质的一个子集可以改善早产的结果。在这种高风险/高 奖励建议我们将测试的核心假设，即蛋白质与大脑的发展， 肺、视网膜、肠和心血管系统由胎盘分泌到胎儿循环中， 极早产儿和极早产儿，给予这些蛋白质的子集改善了 豚鼠早产模型。我们的方法将是确定约5000种蛋白质的丰度， 使用新型慢解离速率，对极早产儿和极早产儿的脐动、静脉和新生儿血液进行检测 改良适体（SOMA）蛋白质组学平台，使我们能够表征早产儿血浆 蛋白质组研究的空前深入。我们将测试这些蛋白质中的一小部分的能力， 使用独特的早产豚鼠模型的结果。这一提议代表了一种范式的转变， 通过关注早产儿出生的宫内环境来探讨早产问题 过早地与基于产后生理学的护理质量分离，而不是优化护理质量 以及早产儿的营养。拟议的工作非常重要，因为它有可能 导致开发从根本上新颖的干预策略，以改善早产儿的结局， 婴儿。

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.