The goal of this study is to elucidate the endogenous hormones and decidual-specific transcription factors controlling the decidualization of human endometrium. Progestin and relaxin (RLX) regulate cell proliferation, differentiation and expression of multiple genes in human endometrial stromal cells. Prolactin (PRL) and phosphorylated insulin- like growth factor binding protein-1 (IGFBP-1) are extensively secreted in decidualized stromal cells. We hypothesize that progestin-dependent and RLX-induced PRL, IGFBP-1 and decidual specific nuclear transcription factor(s) regulate cell growth and differentiation.
Aim 1 is to investigate the effect of endogenous PRL on the mitogenic activities of human endometrial stromal cells. DNA synthesis and transient expression of c-fos and c-myc mRNAs will be examined when PRL synthesis in cells is blocked by a sequence-specific antisense oligomer. This will reveal the role of endogenous PRL on cell proliferation during decidualization.
Aim 2 is to study the mechanism of the inhibitory effect of non-phosphorylated and phosphorylated IGFBP-l isoforms on the mitogenic activities of IGF- I/II (insulin-like growth factor). The competition between IGFBP-1 isoforms and IGF-l receptor for the binding to IGF-I/II and the relative amount of isoforms produced during the process of decidualization will be investigated. The effects of IGF-I/II on the mitogenic activities will be studied in the presence of IGFBP-1 isoform in stromal cells.
Aim 3 is to identify decidual-specific transcription factor(s) by studying the gene transcription of IGFBP-1. Experiments are designed to a) study the transcriptional activities of the promoter of IGFBP-1 gene in human endometrial stromal cells and in endometrial cancer cell line, b) study the binding properties between decidual nuclear proteins to the distal and proximal cis-elements and identify the functional cis-elements essential for the transcription of IGFBP-1 gene in decidual cells, c) identify and characterize the physical properties of decidual specific transcription factor, d) evaluate how the progesterone receptor affects the IGFBP-1 transcription in decidual cells. The outcome of this study will add new dimension to our understanding of the mechanism for decidual cell gene activation and decidualization, a process essential for blastocyst implantation and maintenance of pregnancy. Infertility affects more than 2 million couples in the United States in which failure of implantation and miscarriage may comprise more than 20%. This study will further our understanding the causes of infertility diseases such as luteal phase defect, failure in implantation and recurrent pregnancy loss. Also, this proposal may open new avenues for the development of safer contraceptive methods.
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