The implantation process involves complex interactions between embryonic an uterine cells. The major critical events of the implantation process are: (i) synchronized development of the embryo to the blastocyst stage and establishment of the receptive uterus; (ii) increased capillary permeabilit in the receptive uterus at the site of the blastocyst apposition; (iii) localized decidualization of the uterine stroma immediately following blastocyst attachment; and (iv) controlled invasion of trophoblast cells into the endometrium. Although these critical events are primarily dependent upon temporal and cell type-specific interactions between progesterone (P4) and estrogen (E), the molecular and cellular mechanisms involved in these P4/E regulated processes are not clearly understood. Our working hypothesis is that critical events of implantation, resulting from P4/E interactions in the uterus and/or embryo, are mediated via growth factors in autocrine/paracrine fashion.
Our specific aims are to determine (1) temporal and spatial expression of EGF, TGF-alpha and IGF-I genes in th uterus during proestrus, and on various days of pregnancy and pseudopregnan cy (days 1-8); (2) separate and interactive effects of E and P4 on the expression of these genes in the uterus and deciduum; (3) temporal and cell specific expression of EGF receptors, and IGF-I receptors and binding proteins in the embryo, and in the uterus on proestrus, various days of pregnancy and pseudopregnancy (days 1-8) and under different steroid hormonal conditions; (4) the roles of growth factors on preimplantation embryo development; and (5) the roles of growth factors in uterine cell proliferation, initiation of implantation and decidualization. Analysis of expression of growth factor genes will involve detection of mRNAs by northern blot and in situ hybridization. Immunocytochemistry will be used to localize cell-specific accumulation of growth factor proteins, and western blot and pulse-labeling experiments will be used to determine the sizes and relative rate of synthesis of growth factors. Studies on expression of growth factor receptor genes in the uterus and embryo will be determined by using the polymerase chain reaction (PCR), northern blot and in situ hybridization (mRNAs), as well as immunocytochemistry and ligand binding assays (proteins). While the effects of growth factors on preimplantation embryo development will use an in vitro culture system, roles of these growth factors in uterine functions will be determined by administration of exogenous growth factors of their neutralizing antibodies The results obtained from the proposed study will enhance our understanding of the steroid hormonal modulation of autocrine/paracrine functions of the growth factors in the uterus and embryo during implantation and subsequent decidualization.
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