Placental Proteins and Prematurity - PROJECT SUMMARY/ABSTRACT 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 in a limited number of women, 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 and poor neurodevelopmental outcomes. Emerging evidence in animal studies 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. We reported that 434 proteins are secreted by the placenta into the fetal circulation before 32 weeks of gestation. Remarkably, a substantial number of these proteins could be linked to processes such as angiogenesis, pulmonary development and neurogenesis, suggesting that a subset of these proteins are critical for the normal development of fetal organs that are often injured in premature infants. Inresponse to PAR-23-130 Translational Research in Maternal and Pediatric Pharmacology and Therapeutics, we will test the central hypothesis that supplementation with candidate human placental proteins, i.e., that are secreted into the fetal circulation and associated with the development of the brain, lung, retina, intestine and cardiovascular system, improve outcomes in premature guinea pigs. Our approach will be to induce preterm delivery in guinea pigs, provide them with 24/7 support in a guinea pig neonatal intensive care unit. Pups will either receive a single candidate human placental protein or vehicle by a subcutaneous mini-osmotic pump for 7 days after preterm delivery. We propose three aims: Aim 1: Determine the effect of candidate human placental proteins on mortality and short-term respiratory outcomes in premature guinea pigs. Aim 2: Establish the effect of candidate human placental proteins on short-term neurodevelopmental outcomes in premature guinea pigs. Aim 3: Determine the effect of candidate human placental proteins on long-term lung and neurodevelopmental outcomes in premature guinea pigs. Our proposal is conceptually highly novel because it represents a shift in the paradigm of how to approach prematurity by supplementing with placental proteins supporting organ development. This work may lead to a specific novel intervention that will alleviate perinatal mortality and morbidity and long-term sequelae in extremely premature babies and that is scalable and universally applicable.
