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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Yoshinaga, Koji
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kansas
Schools of Medicine
Kansas City
United States
Zip Code
Chakraborty, Damayanti; Cui, Wei; Rosario, Gracy X et al. (2016) HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia. Proc Natl Acad Sci U S A 113:E7212-E7221
Soares, Michael J; Vivian, Jay L (2016) Tipping the balance toward trophoblast development. Proc Natl Acad Sci U S A 113:5144-6
Imakawa, Kazuhiko; Dhakal, Pramod; Kubota, Kaiyu et al. (2016) CITED2 modulation of trophoblast cell differentiation: insights from global transcriptome analysis. Reproduction 151:509-16
Carey, Timothy S; Cao, Zubing; Choi, Inchul et al. (2015) BRG1 Governs Nanog Transcription in Early Mouse Embryos and Embryonic Stem Cells via Antagonism of Histone H3 Lysine 9/14 Acetylation. Mol Cell Biol 35:4158-69
Kubota, Kaiyu; Kent, Lindsey N; Rumi, M A Karim et al. (2015) Dynamic Regulation of AP-1 Transcriptional Complexes Directs Trophoblast Differentiation. Mol Cell Biol 35:3163-77
Renaud, Stephen J; Chakraborty, Damayanti; Mason, Clifford W et al. (2015) OVO-like 1 regulates progenitor cell fate in human trophoblast development. Proc Natl Acad Sci U S A 112:E6175-84
Cao, Zubing; Carey, Timothy S; Ganguly, Avishek et al. (2015) Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage. Development 142:1606-15
Soares, Michael J (2014) Embryo implantation - coordination of maternal and embryonic adaptations. Int J Dev Biol 58:71-4
Soares, Michael J; Chakraborty, Damayanti; Kubota, Kaiyu et al. (2014) Adaptive mechanisms controlling uterine spiral artery remodeling during the establishment of pregnancy. Int J Dev Biol 58:247-59
Knott, Jason G; Paul, Soumen (2014) Transcriptional regulators of the trophoblast lineage in mammals with hemochorial placentation. Reproduction 148:R121-36