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.

每年，全世界有1,2-18万婴儿，占所有出生的约10％，是早产的（37周之前 妊娠）。基于早产的机制知之甚少，并且有可能 孕酮除外，目前尚无干预措施来防止早产。管理层 在过去的30年中，早产婴儿中有所改善，但是尽管取得了这种进展，早产仍然存在 5岁以下儿童中第二大最常见的直接死亡原因。此外，婴儿出生 早产有新生儿发病率的风险（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，包括慢性肺部疾病，视网膜病，认知 障碍和神经发育结果不良。新兴证据表明，由 胎盘对于正常的胎儿器官发育至关重要。之间最根本的区别之一 胎儿和产后生命是分娩时脐带循环的瞬时终止 胎盘因素（例如蛋白质）早产，对胎儿器官发育至关重要。但是， 人胎盘分泌到胎儿循环中的蛋白质的身份在很大程度上未知。使用 somalogic蛋白质组学平台，我们最近报道说，人类术语分泌了341种蛋白质 胎盘进入胎儿循环。值得注意的是，这些蛋白质中的许多可能与过程有关 例如血管生成和神经发生，表明这些蛋白的子集对于正常 胎儿组织的发展，例如大脑，肺和心血管系统。但是，目前是 尚不清楚这些或其他蛋白质是否由胎盘分泌到妊娠较早的胎儿循环中 如果补充这些蛋白质的子集可以改善早产的预后。在这个高风险/高 奖励提案我们将检验以下中心假设，即蛋白质与大脑的发展相关， 肺，视网膜，肠和心血管系统被胎盘分泌到胎儿循环中 这些蛋白质的一部分，非常早产和给药，改善了A的预后 豚鼠早产模型。我们的方法是确定〜5000蛋白的丰度 脐动脉，静脉和新生儿的血液，非常早产，使用一种新型的缓慢速率 修改的适体（SOMA）蛋白质组学平台，使我们能够表征早产儿血浆 蛋白质组在空前的深度中。我们将测试这些蛋白质一小部分改进的能力 使用独特的豚鼠模型的结果。该提议代表了范式的转变 通过关注婴儿出生早产的宫内环境来解决早产问题 已经过早地分离了，而不是根据产后生理优化护理质量 和早产的营养。拟议的工作非常重要，因为它有可能 导致发展根本新颖的干预策略，以改善早产的结果 婴儿。