The overall objective of this U54 application is to characterize, at molecular and cellular levels, the hormonal pathways that regulate embryo implantation and fertility. Failure of the fertilized embryo to implant into the endometrium is a major cause of infertility. Following its initial attachment to the uterine epithelium, the embryo invades the endometrial stroma, which then undergoes extensive differentiation and remodeling, known as decidualization. Implantation and decidualization are complex processes driven by a cascade of signaling events regulated by the steroid hormones estrogen and progesterone. The central hypothesis of this research program is that defects in these hormonal signaling pathways lead to improper uterine receptivity, decidualization and early pregnancy loss. DNA microarray-based gene expression profiling and receptor-coregulator analyses have revealed novel steroid-regulated pathways, providing important insights into the cellular mechanisms by which implantation is controlled. Combination of this new knowledge with functional analysis in gene knockout mouse models will provide a blueprint of the molecular networks that mediate the hormonal regulation of this process. Extension of these analyses to endometrial tissues obtained from normal women as well as those with endometriosis, a common gynecologic disorder associated with reduced fertility, will provide the important translational component of this research. The program is comprised of four complementary, synergistic projects: (1) Role of C/EBP beta in Uterine Decidualization and Implantation, (2) Nuclear Receptor Co-regulators in Implantation and Uterine Function, (3) Regulation of Stromal Differentiation and Implantation by the BMP2 Pathway, and (4) Endometriosis as a Clinical Model of Predecidual Dysfunction. Investigators will be aided by an Administrative Core that will oversee inter-project interactions and data sharing, and a Microscopy Core that will provide gene and protein expression analyses in cells and tissues. In summary, the results of our studies should improve understanding of the mechanisms and cellular pathways that control implantation and help identify factors that underlie infertility in women with endometriosis. They should also aid in developing new molecular diagnostic tools for screening endometrial dysfunction and enable targeted therapeutic strategies for the treatment of infertility.
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