The preimplantation phase of mammalian embryo development proceeds in several stages. Starting with the one-cell zygote, mitosis gives rise to a multicellular embryo that differentiates into a morula and then to the blastocyst. The blastocyst is characterized by the differentiation into two different compartments, the inner cell mass (ICM) and the trophectoderm. The development and function of the trophoblasts giving rise to the placenta are under the control of maternal and embryonic factors. Steroid hormones and other factors help to modulate the responsiveness of the uterus to implantation. Studies of mammalian embryos in culture have provided evidence for the production of autocrine growth factors as well as paracrine interactions between the ICM and trophectoderm. One of these factors, acrogranin (the granulin/epithelin precursor) has an important role in the development of preimplantation mouse embryos in culture. In this proposal, the broad, long-term objective is to determine the role of the acrogranin gene in regulating the development of pre- and peri-implantation mammalian embryos. The goals of this project are:
Specific Aim 1. Characterize the role of acrogranin in preimplantation embryo development.
Specific Aim 2. Examine the effects of acrogranin on the trophectoderm stem (TS) cell model.
Specific Aim 3. Determine the signal transduction pathways used for acrogranin signaling in blastocysts.
Specific Aim 4. Determine whether acrogranin is part of a paracrine loop regulating Oct4, leukemia inhibitory factor, and fibroblast growth factor-4 signaling in mouse blastocysts. Studies on the role of acrogranin in trophoblast growth and differentiation will lead to a better understanding of the molecular bases of human placental disorders such as """"""""missed abortions"""""""" (pregnancy losses in the first two months of gestation), some types of intrauterine growth retardation, and pre-eclampsia.
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