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 I have identified distinct types of placental calcification that vary between pregnancy types. I have developed models of how loss or dysfunction of Slc20a1 and Slc20a2 could lead to preeclampsia; here I propose aims that will test these models in mouse and human and provide fundamental mechanistic insights into phosphate transporter biology and placental pathophysiology. As a postdoctoral trainee during the mentored (K99) phase of the research program, I will build upon my preliminary data and obtain the training necessary to test the hypothesis that placental dysfunction and preeclampsia can be caused by dysregulated phosphate metabolism that disrupts placental development and function, and promotes the deposition of placental calcification. I will test my prosed models of Slc20a1 and Slc20a2 yolk sac and placental phosphate transport, and publish these findings during the K99 phase. After I have transitioned into the independent (R00) phase, I will continue to investigate molecular mechanisms of Slc20a1 and Slc20a2 function. I will also test hypotheses aimed at determining how loss of Slc20a1 and Slc20a2 could lead to placental dysfunction, how calcification impacts placental function, and whether candidate pro-calcific markers are diagnostic tools for placental calcification-associated preeclampsia.

Public Health Relevance

Preeclampsia (PE), a life-threatening pregnancy-specific syndrome, is caused by abnormal blood vessel development in the placenta. PE can lead to premature deliveries, large medical costs, and even death. People that develop PE have decreased levels of the phosphate transporters Slc20a1 and Slc20a2 in their placenta, and I have found that mice that lack Slc20a1 or Slc20a2 display poor blood vessel development, signs of PE, and placental calcification (deposition of phosphate-containing minerals). The long-term goal of this research project is to improve our understanding of PE by determining how loss of Slc20a1 and Slc20a2 could lead to placental dysfunction, and how placental calcification impacts placental function.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Career Transition Award (K99)
Project #
1K99HD090198-01
Application #
9222251
Study Section
Obstetrics and Maternal-Fetal Biology Subcommittee (CHHD-B)
Program Officer
Ilekis, John V
Project Start
2017-03-01
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
$107,984
Indirect Cost
$7,999
Name
University of Washington
Department
Engineering (All Types)
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195