Project Summary: I aim to establish a biomedical research lab that investigates mechanisms of placental development and pathophysiology. Dr. Alan Guttmacher recently identified the placenta as “the least understood human organ” when discussing the Human Placenta Project, a new initiative of the National Institute of Childhood Health and Human Development (Kaiser J. 2014. Science 344(6188):1073). Placental dysfunction and resulting syndromes are poorly understood despite the clear significance to human health. Impaired placental function can lead to fetal growth restriction and is linked to preeclampsia, a pregnancy specific life-threatening hypertensive syndrome within unknown etiology. Preeclampsia is a leading cause of maternal and neonatal death. It occurs in 3-8% of pregnancies, and ~4% of these cases result in mortality. Other cases lead to premature birth, developmental disorders in offspring, increased risk for cardiovascular and kidney diseases later in life for mothers, and substantial health care costs. Unfortunately, the number of preeclampsia cases is increasing. Stephen Hodgins, Deputy-in-Chief of Global Health: Science and Practice, recently published an editorial titled “Pre-eclampsia as an Underlying Cause for Perinatal Deaths: Time for Action” (Hodgins S. 2015. GHSP; 3(4):525-527), highlighting this important global public health issue. A better understanding of the placenta is greatly needed in order to diagnose, treat, and prevent preeclampsia and other health issues resulting from placental dysfunction. My work will address several key unknowns in placental development and pathophysiology. I will begin by determining molecular mechanisms of maternal-fetal phosphate transport. Phosphorus is an essential nutrient and it is required for several processes in growth and development, such as DNA and cell membrane structure, bone deposition, oxidative phosphorylation, and others. Remarkably, the molecular mechanisms and proteins that regulate maternal-fetal phosphate transport remain unknown. I have identified a likely family of maternal-fetal phosphate transporters and developed loss of function mouse models that revealed specific developmental requirements. PiT-1 loss results in embryonic lethality, decreased endocytosis, and impaired angiogenesis (Wallingford et al. 2014. Mech. Dev. 133:189-202). PiT-2 deficiency results in fetal growth restriction, decreased bone density, and abundant placental calcification (Wallingford et al. Reprod. Biol. and Wallingford et al. Brain Pathology – both in process). The PiT-2 null mouse is the first and only placental calcification model available. My data suggests that PiT-2 mediated anti-calcific mechanisms may play a key role in preventing placental dysfunction, and clinical studies have indeed correlated altered expression levels of PiT-1 and PiT-2 with preeclampsia (Yang et al. 2014. Mol. Reprod. & Dev. 81:851-860). Further, calcification of the placenta is frequently observed in humans, and...