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.
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