Placental Proteins and Prematurity

每年，全世界有1200-1800万婴儿早产(37周前)，约占所有新生儿的10% 孕期)。人们对早产的机制知之甚少，而且有可能 除了黄体酮，目前还没有预防早产的干预措施。管理层 在过去的30年里，早产儿的情况有所改善，然而，尽管有这种进步，早产儿仍然存在。 5岁以下儿童死亡的第二大直接原因。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，包括慢性肺部疾病、视网膜病变、认知 损害和不良的神经发育结果。新出现的证据表明， 胎盘是胎儿正常器官发育的关键。两者之间最根本的区别之一是 胎儿和出生后的生命是分娩时脐带循环的瞬间中断，剥夺了 早产儿的胎盘因素，如蛋白质，对胎儿器官发育至关重要。然而， 人类胎盘分泌到胎儿循环中的蛋白质在很大程度上仍不清楚。使用 SomaLogic蛋白质组平台，我们最近报道了341种蛋白质是由人类术语分泌的 胎盘进入胎儿循环。值得注意的是，这些蛋白质中的大量可能与过程有关 例如血管生成和神经生成，这表明这些蛋白质的一个子集对正常 胎儿组织的发育，如脑、肺和心血管系统。不过，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部分可以改善早产儿的结局。在这种高风险/高风险中 奖励建议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到胎儿循环中。 极早产儿和极早产儿以及使用这些蛋白质的子集可以改善预后 豚鼠早产模型。我们的方法将是确定~5000个蛋白质的丰度 极早产儿和极早产儿的脐动、静脉和新生儿血液，使用一种新的减速率 改良适体(SOMA)蛋白质组学平台，使我们能够表征早产儿血浆 蛋白质组研究达到了前所未有的深度。我们将测试这些蛋白质中的一小部分改进的能力 使用一种独特的早产豚鼠模型的结果。这一提议代表了如何 关注婴儿早产的宫内环境探讨早产问题 过早地脱离了，而不是基于出生后生理学来优化护理质量 以及早产儿的营养状况。拟议的工作意义重大，因为它有可能 导致开发全新的干预策略，以改善早产儿的预后 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.