It is important to make a healthy placenta. Insufficient trophoblast proliferation or an imbalance between proliferation and differentiation may lead to pre-edampsia, IUGR or spontaneous abortion early after implantation of the embryo into the uterus, the time when most human conceptuses are lost. Our long term goal is to understand the signal transduction pathways that transduce intercellular signals into the trophoblast and induce proliferation. We have previously found that FGF input is required to produce trophoblast in the implanting embryo. We propose here to define the signal transduction pathways mediating trophoblast proliferation by promoting FGF-induced trophoblast proliferation and then testing several inhibitors of candidate transduction pathways to find which pathway(s) mediate the proliferative signal. In addition, we will block FGF-induced proliferation and then test for which rate-limiting enzyme genes in several signal transduction pathways are sufficient to re-activate the cell cycle. We also intend to define the FGF-induced signaling pathways that lead to proliferation compared with morptiogenetic events/differentiation. Since the first IVF baby, only 300,000 of 1,500,000 IVF attempts have resulted in a successful pregnancy. The majority of loss of human embryos is near the time of implantation. Other later loss of embryo/fetus loss due to preeclampsia and IUGR may also begin early at the time of implantation. Much of the loss is due to improper growth and differentiation of the placenta. Improved IVF requires an understanding of the mechanisms that mediate growth in the trophoblast lineage that enables placental function. The mouse is an excellent model to study implantation in humans. Therefore, the proposed studies should lead to improvement in methods to facilitate placentation and improve IVF and produce protocols for remediation of common defects in pregnancy such as pre-eclampsia and IUGR.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD040972-05
Application #
6941772
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Yoshinaga, Koji
Project Start
2001-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
5
Fiscal Year
2005
Total Cost
$268,200
Indirect Cost
Name
Wayne State University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Puscheck, Elizabeth E; Awonuga, Awoniyi O; Yang, Yu et al. (2015) Molecular biology of the stress response in the early embryo and its stem cells. Adv Exp Med Biol 843:77-128
Xie, Yufen; Zhou, Sichang; Jiang, Zhongliang et al. (2014) Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency. Stem Cell Res 13:478-91
Slater, Jill A; Zhou, Sichang; Puscheck, Elizabeth Ella et al. (2014) Stress-induced enzyme activation primes murine embryonic stem cells to differentiate toward the first extraembryonic lineage. Stem Cells Dev 23:3049-64
Rappolee, Daniel A; Xie, Yufen; Slater, Jill A et al. (2012) Toxic stress prioritizes and imbalances stem cell differentiation: implications for new biomarkers and in vitro toxicology tests. Syst Biol Reprod Med 58:33-40
Awonuga, A O; Zhong, W; Abdallah, M E et al. (2011) Eomesodermin, HAND1, and CSH1 proteins are induced by cellular stress in a stress-activated protein kinase-dependent manner. Mol Reprod Dev 78:519-28
Xie, Y; Awonuga, A O; Zhou, S et al. (2011) Interpreting the stress response of early mammalian embryos and their stem cells. Int Rev Cell Mol Biol 287:43-95
Zhou, S; Xie, Y; Puscheck, E E et al. (2011) Oxygen levels that optimize TSC culture are identified by maximizing growth rates and minimizing stress. Placenta 32:475-81
Xie, Yufen; Abdallah, Mazen E; Awonuga, Awoniyi O et al. (2010) Benzo(a)pyrene causes PRKAA1/2-dependent ID2 loss in trophoblast stem cells. Mol Reprod Dev 77:533-9
Zhong, W; Xie, Y; Abdallah, M et al. (2010) Cellular stress causes reversible, PRKAA1/2-, and proteasome-dependent ID2 protein loss in trophoblast stem cells. Reproduction 140:921-30
Rappolee, Daniel A; Awonuga, Awoniyi O; Puscheck, Elizabeth E et al. (2010) Benzopyrene and experimental stressors cause compensatory differentiation in placental trophoblast stem cells. Syst Biol Reprod Med 56:168-83

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