The human endometrium undergoes a highly regulated sequence of proliferation, differentiation, and ultimately proteolytic breakdown and shedding of tissue with each menstrual cycle. Metalloproteinases *MMPs) are intimately involved in the breakdown of endometrial tissue at the time of menstruation and also play a critical role during the process of implantation. Attachment and invasion of the implanting conceptus requires the participation of MMPs produced by both the embryo and endometrial cells. Pathological conditions such as endometriosis and adenomyosis are examples of inappropriate invasion by endometrium. An essential component of endometriosis is the attachment and invasion of endometrial fragments through the mesothelial cell layer into the underlying stroma. This process is dependent on expression of specific MMPs by the endometrial tissue. Recent studies have demonstrated that attachment and invasion of endometrial tissue can only occur with intact endometrial tissue fragments containing both epithelial and stromal components. This suggests that an important interaction between the two cell types is needed to allow this invasive event to occur. We have recently identified a protein in human endometrium and endometriotic lesions called extracellular and matrix metalloproteinase inducer (EMMPRIN). EMMPRIN is also expressed by uterine epithelial cells and trophoblast cells in the mouse and appears to play an important role in implantation since the EMMPRIN knockout mouse is infertile due to an implantation defect. We hypothesize that EMMPRIN produced the uterine epithelial cells regulates production of MMPs by uterine stromal cells and localization of MMPs within the endometrium.
The specific aims of this proposal are: 1. To determine the role of EMMPRIN in regulating MMP production and cellular adhesion by the mouse embryo. 2. To determine whether the failure of implantation in EMMPRIN knockout mice is due to impaired adhesion and MMP production by trophoblast or endometrial stromal cells. 3. To determine whether EMMPRIN regulates the expression of MMPs by eutopic and endometriotic uterine stromal cells and/or serves as a docking protein for specific MMPs produced by these cells. The results of these studies will provide important insights into epithelial-stromal cell communication in the uterus that may clarify the mechanisms involved in implantation as well as pathogenic events such as endometriosis.
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