Uterine endometrium undergoes cyclic mitoses and differentiation in response to circulating gondal steroids acting primarily through growth factor mediators. It is the tissue in which implantation occurs, and abnormal endometrial development can result in infertility and poor placentation. A long-term goal of our laboratory is to elucidate mechanisms underlying normal and abnormal endometrial development and decidual: trophoblast interactions so that therapies can be designed to treat endometrial dysfunctions underlying these processes. The insulin like growth factors (IGFs) and their binding proteins (IGFBPs) play a central role in cyclic endometrial development and implantation. IGF-II is abundant in secretory endometrium and in the fetal trophoblast. IGFs are mitogenic to endometrial cells and affect their differentiated functions, and they also modulate trophoblast steroid and protein hormone production. IGF actions in most tissues are modulated by IGFBPs. IGFBP-1 is a major protein and the major IGF binding protein produced in endometrium during the peri-implantation period and in the endometrium (decidua) of pregnancy. We have found that IGFBP-1 binds to cytotrophoblasts, that trophoblast invasion in decidualized endometrial stroma is inhibited in the presence of IGFBP-1, and that high levels of IGFBP-1 are at the decidual-placental interface of pregnant women with shallow placental invasion, all suggesting that IGFBP-1 functions as an inhibitor of placental invasion in humans. This grant focuses on the role of IGFBP-1 in regulating IGF actions in endometrium and trophoblast and on its potential role, independent of IGFs, in implantation, using biochemical and molecular approaches and human endometrial and cytotrophoblast cells in culture.
The specific aims are to elucidate (1) mechanisms underlying IGFBP-1 regulation of IGF-II action in human endometrium and trophoblast, (2) the roles of IGFBP-1 in implantation and placental invasion by defining the interactions and cellular processes affected by IGFBP-1 binding to trophoblasts and (3) a clinical application of IGFBP-1 in a pregnancy disorder associated with shallow placentation. We have chosen the human model because most aspects of endometrial cyclic development and implantation are unique to humans and elucidation of mechanisms underlying these processes may provide insight into abnormalities that affect pregnant women and their developing fetuses.
| Tierney, Emily P; Tulac, Suzana; Huang, Se-Te Joseph et al. (2003) Activation of the protein kinase A pathway in human endometrial stromal cells reveals sequential categorical gene regulation. Physiol Genomics 16:47-66 |
