The initiation of pregnancy requires a precisely timed synchrony between endometrial development and the implanting blastocyst. This """"""""receptive window"""""""" is initially dependent on estrogen and progesterone. However, signals from the developing embryo further modify the receptive uterus. During the previous funding period we addressed this issue in a non-human primate model. We demonstrated that in addition to the specific changes that are induced by estrogen and progesterone during the window of receptivity, infusion of chorionic gonadotrophin (CG) in a manner that mimics blastocyst transit further modulates the uterine environment. Changes are evident in all three major cell types i.e., the luminal epithelium, glandular epithelium and stromal fibroblasts. The modulation of the cytoskeletal architecture in stromal fibroblasts and the increase in secretory activity in glandular epithelial cells are regulated by CG acting directly on the endometrium, independent of the ovary. Furthermore these responses are suppressed when the progesterone receptor is antagonized. Since our in vivo studies have clearly demonstrated a direct effect of CG on modulating uterine receptivity, we now propose a series of studies to determine the function of two gene products that are induced in stromal fibroblasts in response to CG stimulation. Stromal Cell Protein (SCP) and Notch-1 are both expressed in stromal cells and their expression is regulated both in vivo and vitro by CG. The first Specific Aim is focused on determining the mechanisms by which SCP activates Recombination Activating Gene in immune cells, which in turn may be responsible for altering the phenotype of lymphocyte populations within the endometrium. We hypothesize that these regulating mechanisms play a central role in providing immune tolerance to the fetal allograft. In the second Specific Aim we propose to determine the role of Notch-1 to inhibit apoptosis in stromal fibroblasts. In addition, Notch-1 is also able to influence the commitment to phenotypic differentiation within the lymphoid lineage. Thus, these studies will provide insight into the mechanisms by which stromal fibroblasts play an important role during the establishment of pregnancy. Understanding the complex immune and cell differentiation mechanisms within the uterine environment during early pregnancy has direct relevance to our ability to identify causes of infertility, pregnancy failure and other possible causes of infertility in women.
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