The role of prenatal nutrition in placental gene regulation and spontaneous preterm birth

PROJECT ABSTRACT A fundamental question bridging the fields of nutrition and developmental biology is identifying nutritional requirements during pregnancy that support optimal fetal development. The placenta is the sole source of nutrients for the fetus and prenatal nutrition influences placental function. While prenatal nutrition plays a vital role in programming maternal and infant health outcomes, the roles of essential nutrients in the placenta are poorly understood. Moreover, nutrition recommendations for pregnancy were set without regard for preventing adverse pregnancy outcomes. The proposed research seeks to address these knowledge gaps to understand how nutrient–gene interactions influence placental biology and pregnancy outcomes. I propose to build a genome-scale nutrient regulatory network (NRN) of the human placenta and leverage it to identify real-world nutrient mixtures associated with an important adverse pregnancy outcome, spontaneous preterm birth (sPTB). My research plan builds on my background in developmental nutrition and ‘omics analysis. During the K99 mentored phase, I will engage in didactic training in placental biology, network analysis, and molecular epidemiology. I have recruited a multidisciplinary mentorship and advisory team with a strong record of collaboration, who will support my success in executing the proposed aims. I will establish and computationally validate a placental NRN using existing nutrient intake data collected during mid-pregnancy and gene expression in placentas collected at birth in a large, well-characterized pregnancy cohort (Aim 1). In the R00 independent phase, I will harness training in placental biology, network analysis, and molecular epidemiology to investigate nutritional regulation in sPTB. I will use the NRN and our published transcriptomic signature of sPTB to identify candidate nutrients and real-world nutrient mixtures associated with sPTB to validate the candidate nutrients in a nationwide consortium of pregnancy cohorts (Aim 2). This aim will provide specific insight into the most important nutrients as potential targets in interventions to prevent sPTB. In parallel, I will use causal inference methods to estimate effects in silico of public health interventions using widely available, over-the-counter prenatal vitamin/mineral supplements (PV) (Aim 3). I will identify a real-world nutrient mixture associated with low sPTB risk and use reported nutrient intakes to estimate an intervention that will optimally shift nutrient intakes and likewise evaluate its effects as a public health intervention. This aim will estimate the effects of a nationwide PV intervention compared to empirical results and provide direct translational value. Successful completion of this proposal will represent a significant step towards understanding how prenatal nutrition influences placental function and will identify real-world nutrient mixtures that contribute to adverse outcomes like sPTB. Finally, this K99/R00 will provide mentorship and training needed to establish and lead an independent lab investigating nutritional regulation of development using network biology, molecular epidemiology, and ‘omics approaches.