Miscarriage causes termination of 15-20% of implantation-confirmed pregnancies. Majority of miscarriages occur during the first trimester of pregnancy and defective development of trophoblast cell lineage, which assures embryo implantation and placentation, is one of the leading causes for early pregnancy loss. However, we have a poor understanding of molecular mechanisms that regulate trophoblast progenitor differentiation and function in early post-implantation embryos. Our published and preliminary studies establish that GATA family transcription factors, GATA2 and GATA3, are conserved in trophoblast progenitors across mammalian species and are critical regulators to specify and maintain trophoblast lineage during early mammalian development. The overarching goal of this proposal is to further define GATA factor- mediated transcriptional mechanisms that regulate development and proper function of specialized trophoblast cell types at the maternal-fetal interface.
Three specific aims are proposed.
Aim 1 will study a Gata2/Gata3 double knockout (Gata2-/-/Gata3-/-) mouse model and GATA-mutated rat models to test the hypothesis that cell-autonomous functions of GATA factors are essential to establish differentiated cell-fate in the trophoblast progenitors of a developing placenta.
Aim 2 will perform global gene expression analyses in primary trophoblast cells of developing placenta with or without GATA mutations. The goal is to test the hypothesis that GATA factors establish differential transcriptional circuitry in trophoblast stem/progenitor cells vs. differentiated trophoblast cells, thereby specifying trophoblast subtypes.
Aim 3 will study GATA-mediated regulation of gene expression in human trophoblast cells. The objective is to test the hypothesis that GATA2 and GATA3 are essential to maintain a core TSC-specific transcriptional program in trophoblast progenitors across mammalian species, including human villous cytotrophoblast (vCTB) progenitors of a human placenta. We will also test whether pregnancy associated disorders involve altered GATA factor-mediated gene regulation in vCTBs.

Public Health Relevance

to Public Health: Defect in trophoblast lineage development results in early pregnancy loss or leads to pregnancies that are associated with intrauterine growth restriction or preeclampsia, which are leading causes of maternal death and premature birth. These are major public health concerns. One of the leading causes for early pregnancy loss is defective development of trophoblast cell lineage, which assures embryo implantation and placentation, Therefore, a better understanding of trophoblast cell lineage development and function is critical to gain insights into important features of pregnancy loss and pregnancy associated disorders.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD062546-07
Application #
9538076
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Eisenberg, Esther
Project Start
2010-08-16
Project End
2022-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kansas
Department
Pathology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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Home, Pratik; Kumar, Ram Parikshan; Ganguly, Avishek et al. (2017) Genetic redundancy of GATA factors in the extraembryonic trophoblast lineage ensures the progression of preimplantation and postimplantation mammalian development. Development 144:876-888
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Paul, Arindam; Paul, Soumen (2014) The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers. Front Biosci (Landmark Ed) 19:605-18

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