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.

R21HD104914

2021-09-24

2023-08-31