The establishment of pregnancy is dependent upon the execution of a precise dialog between maternal and embryonic structures. The setting for the maternal-embryonic communication is within the uterus. Embryonic survival, growth, and development within the uterus are dependent upon development of a specialized population of cells on the surface of the embryo. These cells are the earliest constituents of the trophoblast lineage and have the unique capacity to further differentiate into cells with the ability to conver the maternal environment into a hospitable site for embryonic development, including restructuring maternal vasculature to facilitate nutrient flow and acquisition of efficient nutrien transport to the fetus. Appropriate development of the trophoblast lineage is essential for the establishment of pregnancy. Disruptions in trophoblast lineage determination, expansion, and differentiation are at the core of early pregnancy loss. We hypothesize that the regulation of these fundamental cellular processes is a key to discovering the etiology of early pregnancy loss. Consequently, it is imperative that we expand our understanding of molecular mechanisms controlling development of the trophoblast lineage. The proposed programmatic effort consists of three research projects directed toward elucidating molecular mechanisms regulating trophoblast lineage development. The emphasis is on transcriptional and epigenetic mechanisms (transcription factor, histone modifications, chromatin organizer) controlling stem cell populations. RESEARCH PROJECT I evaluates the role of TEAD4 in the regulation of the trophoblast lineage;RESEARCH PROJECT II assesses the contributions of SATB proteins to the maintenance of the trophoblast stem cell stem state;RESEARCH PROJECT III investigates the involvement of histone H3K9 methylation in the regulation of trophoblast lineage development. The experimentation utilizes rodent stem cell in vitro and in vivo models, early embryo manipulation in rodents, and assortment of different methodologies in transcriptional and epigenetic analysis and will be facilitated by the availability of cost-effective administrativ and research cores. The proposed programmatic effort is highly interactive and benefits from the unique expertise of each participant.

Public Health Relevance

Early pregnancy loss is a significant health concern. Trophoblast cells are key contributors to establishing a successful pregnancy. Elucidation of molecular mechanisms controlling development of the trophoblast lineage is a valuable approach for understanding the etiology of early pregnancy loss and discovering diagnostic and therapeutic strategies for the detection, treatment, and prevention of the disease.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD079363-01A1
Application #
8743034
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Yoshinaga, Koji
Project Start
2014-07-24
Project End
2019-06-30
Budget Start
2014-07-24
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Kansas
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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Ilekis, John V; Tsilou, Ekaterini; Fisher, Susan et al. (2016) Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Am J Obstet Gynecol 215:S1-S46

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