Over the past 14 years the applicants lab has investigated decidualization of human endometrial stromal interactions between the human trophoblast and the maternal decidua in an effort to understand paracrine mechanisms operating in the placental bed during the invasive phase of human implantation. In particular, they have focussed on the insulin-like growth factor (IGF) family and its role in human implantation. IGF-II is abundantly expressed by the invading trophoblast, and it regulates maternal decidual modulators of invasion [IGF binding protein-l and tissue inhibitor of metalloproteinase-3,TMP-3]. In addition, the investigators have pursued a global approach to gene profiling of human endometrial stromal cells during the process of decidualization in response to progesterone and to cAMP, and gene profiling of human endometrial biopsies, obtained in the implantation window and timed to the LH surge, in search of potential markers of uterine receptivity. These studies have revealed marked upregulation of IGF signaling cascade members and candidate genes for uterine receptivity and stromal decidualization. The underlying hypothesis of this proposal is that trophoblast-derived IGF-II acts on neighboring maternal endometrial stromal cells and regulates maternal modulators of trophoblast invasion.
The specific aim i s to investigate mechanisms underlying IGF-II actions an human endometrial stromal cells with a focus on signaling pathways and gene expression relevant to human implantation. The investigators shall validate signaling pathway members in human endometrium and test the hypothesis that the PI3 kinase pathway and phosphodiesterase 3B (PDE3B) mediate IGF-II effects on decidualized endometrial stromal cell modulators of trophoblast invasiveness. Effects of IGF-II signaling inhibitors on trophoblast invasion in vitro will be investigated as """"""""proof of principle"""""""" and as a model for targeted drug development to enhance or inhibit trophoblast invasion. Finally, the investigators propose a gene discovery approach to investigate IGF-II actions on human endometrial stromal cell global gene expression. This will provide the Cooperative UO1 Program with a database of genes clustered by function expressed in decidualized endometrial stromal cells that are regulated by IGF-II. This information can be used to investigate trophoblast-decidual interactions and enable targeted drug development for therapeutic intervention or prevention of abnormalities in trophoblast invasion, including infertility, ectopic pregnancy, and pre-eclampsia. The investigators work with the human model because of the uniqueness of implantation in humans.
