During early pregnancy, the uterine stromal cells undergo extensive proliferation, differentiation and remodeling, known as decidualization. This hormonally induced cellular transformation is an essential prerequisite for embryo implantation. It is evident that perturbations in this process lead to dysfunctions in uterine receptivity that result in female infertility. The overall objective of Project I is to explore the functional role of C/EBPb, a transcription factor, as a unique regulator of decidualization.
The specific aims of this study are to: 1. Investigate the mechanisms by which C/EBPb controls stromal proliferation during decidualization. A mouse model lacking C/EBPb revealed that its deficiency leads to a mitotic arrest of the stromal cells. To analyze this defect, the expression and function of the cell cycle regulatory molecules that control mitotic entry and progression through this phase will be examined in the mutant stromal cells. 2. Analyze the molecular basis of regulation of the extracellular matrix (ECM) by C/EBPb during stromal differentiation. Gene expression profiling studies revealed that C/EBPb is a major regulator of the stromal ECM formation during decidualization. We will examine whether this transcription factor regulates ECM-related genes directly by interacting with their promoters or indirectly by modulating TGF-b signaling. 3. Determine whether C/EBPb-regulated ECM components control stromal differentiation. Using an in vitro decidualization system and various loss-of-function approaches, the roles of C/EBPb-regulated genes on stromal differentiation and ECM assembly will be addressed. 4. Investigate the function of C/EBPb in human endometrial stromal cell differentiation. Since C/EBPb is found to control the decidualization of human stromal cells in vitro, DMA microarray analysis will be used to identify its regulatory pathways in these cells. The expression of C/EBPb and its selected target genes will be examined in endometrial stromal cells obtained from women with endometriosis, a gynecological disorder in which aberrant decidualization is thought to result in infertility. The exploration of the unique pathways that work downstream of C/EBPb to control proliferation and differentiation of uterine stromal cells will provide a better understanding of decidualization and implantation. The proposed analysis of C/EBPb signaling in endometriotic tissues is likely to provide important insights into the molecular and cellular malfunctions associated with infertility in these subjects
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