In early placental development, trophoblastic cells line the implantation site and invade the maternal decidua, thus establishing adequate blood flow between mother and fetus. Shallow trophoblast invasion has been associated with preeclampsia, a complex disease of pregnancy that can have devastating consequences on mother and child, and can result in Intrauterine Growth Restriction (IUGR). Despite the importance of trophoblast invasion, little is known about the genomic regions responsible for regulating it. The proposed project will allow the candidate to combine genomics, computational biology, and molecular biology to study the regulatory mechanisms underlying trophoblast invasion. During the mentored phase of this project, the candidate will uncover novel genes, genomic regions, and pathways regulating trophoblast invasion. Specifically, she will: (1) develop resources and computational tools that will aid in studying placental development and disease;and (2) identify genes and genomic regions active during trophoblast invasion. Completion of the mentored phase will ensure training in: setting up a lab with a computational infrastructure;further technical skills in computational analysis;additional molecular biology techniques to study placental development and perform genome editing;and career development skills relevant to being a successful independent principal investigator. The candidate's training environment is ideal for carrying out the proposed studies. Her mentor, mentoring committee, and Stanford University collectively provide an excellent training program, extensive interactions among a variety of research groups, and a well-supported research environment. The resources she builds, the tools she develops, the data she generates, and the skills she acquires during the mentored phase will be the foundation of her independent research. During the independent phase of this project, the candidate will focus her trophoblast invasion research on the HIF pathway, and will demonstrate the functional importance of HIF regulated regions. Specifically, she will: (1) identify HIF regulated genes and genomic regions during trophoblast invasion;(2) validate the importance of HIFs in regulating enhancers in invasive mouse and human placental cells;and (3) measure enhancer contribution to trophoblast migration and invasion. The proposed studies will advance our limited understanding of the mechanisms of trophoblast invasion and may provide insights into the etiology of preeclampsia and IUGR. The K99/R00 award will help the candidate achieve her ultimate goal of establishing a research program based on combined computational and experimental approaches to studying the mechanisms behind trophoblast invasion.
Knowledge of the mechanisms underlying trophoblast invasion, a process that takes place in early pregnancy and is essential for establishing adequate blood flow between mother and fetus, is crucial to understanding pregnancy disorders. Defects in trophoblast invasion have been associated with preeclampsia, Intrauterine Growth Restriction (IUGR), and other diseases of pregnancy that can have devastating consequences on mother and child. This study will focus on the role of Hypoxia Inducible Factor (HIF) in trophoblast invasion, will identify HIF-regulated elements that are critical to the invasin process, and may provide insights into the etiology of preeclampsia and IUGR.