Placental NAD and its effect on labor onset - PROJECT SUMMARY Preterm birth is the leading cause of death in children through age 5 worldwide, and our lack of effective therapies for preterm labor reflects major gaps in our understanding of the mechanisms regulating labor onset, both at term and preterm. While a tremendous body of work recognizes fundamental roles of NAD+ in diverse organ systems, extension of such studies to the placenta is an obvious gap. Having previously demonstrated that loss of metabolic homeostasis in the placenta promotes labor onset, this project will test the hypothesis that NAD+ is a key effector of placental metabolism whose dysregulation is coupled with labor onset. Aim 1 is designed to define the disposition of NAD+ and its precursors across the maternal-fetal interface, via real-time flux experiments using radioisotope-labeled precursors in primary trophoblasts and in pregnant mice in vivo. These experiments will additionally make use of a mouse model with targeted placental deletion of Nampt, a key enzyme in the NAD+ salvage pathway. Aim 2 is designed to elucidate mechanisms by which nicotinamide supplementation may delay labor onset in mice, by interrogating putative pathways in cellular and in vivo models. Bringing together an innovative multidisciplinary mentorship team, this project will achieve mechanistic interrogation of placental metabolism and molecular biology using an array of model systems. Moreover, this project will provide a robust career development platform for the candidate, spanning: 1. mastery of techniques for isotope-labeled flux experiments, 2. didactic education in placental biology as well as mass spectrometry and related computational methods, 3. access to professional activities including grant- writing and leadership workshops, and 4. graduated exposure to responsibilities such as mentoring young trainees and reviewing manuscripts for journals in the field. Career guidance will be provided by an Advisory Committee in addition to the mentor/co-mentor/collaborator team. In the setting of exceptional institutional commitment and a training plan optimized for a targeted new skill set, this project will comprehensively provide a rich scientific platform for launching the candidate’s independent career further investigating placental metabolism and adverse outcomes in pregnancy.
