EMMPRIN Regulates Tissue Remodeling in the Endometrium

子宫内膜异位症的定义是在异位部位存在子宫内膜腺体和间质，最常见的是 在盆腔的腹膜上子宫内膜异位症的发病率估计在30- 60%的女性患有盆腔疼痛和不孕症，相关的医疗费用也是巨大的。 异位子宫内膜碎片的植入被认为受细胞因子和生长的调节 免疫细胞和子宫内膜细胞自身局部分泌的因子。不孕症是 通常与子宫内膜异位症相关的一种疾病，至少部分是由于在位基因表达的改变， 子宫内膜这些改变的基因表达模式导致子宫内膜环境， 接受植入的胚胎，不能维持其发展。我们已经证明了糖基化， 称为细胞外基质金属蛋白酶诱导因子（EMMPRIN）的跨膜蛋白在大肠杆菌中表达。 人和小鼠子宫，并调节子宫基质细胞的金属蛋白酶的产生。 EMMPRIN表达在患有子宫内膜异位症的妇女和狒狒的在位和异位子宫内膜中上调， 子宫内膜异位症使用小鼠EMMPRIN敲除模型，我们已经表明，在缺乏EMMPRIN的小鼠中， 表达，子宫基质细胞经历对油注射的响应的过早蜕膜化， 不能生育EMMPRIN抑制子宫基质细胞蜕膜化表达 标志物如碱性磷酸酶-2，并通过以下途径诱导几种细胞因子和趋化因子的表达： 这些细胞。因此，EMMPRIN似乎是子宫内膜重塑的多功能调节剂。我们 具体目标是：#1：确定子宫上皮细胞分泌全长可溶性EMMPRIN的方式 以及EMMPRIN如何通过调节细胞因子、趋化因子和血管生成因子的产生 子宫基质细胞#2：确定EMMPRIN如何调节子宫内膜增殖和蜕膜化 间质细胞，并阐明EMMPRIN在这些细胞中使用的细胞内信号通路。 #3：确定EMMPRIN对间皮细胞上皮-间充质转化的影响。 本研究将通过对EMMPRIN在子宫内膜碎片侵袭中的作用的研究来阐明EMMPRIN在子宫内膜碎片侵袭中的作用。 间皮炎，导致建立增生性病变。它们也将有助于解释为什么 EMMPRIN在在位子宫内膜的表达可导致着床失败。

Endometriosis is defined as the presence of endometrial glands and stroma at ectopic sites, most commonly on the peritoneum within the pelvic cavity. The incidence of endometriosis is estimated to range from 30- 60% in women with pelvic pain and infertility and the associated health care costs are enormous. Implantation of endometrial fragments at ectopic sites is thought to be regulated by cytokines and growth factors secreted locally by immune cells as well as by the endometrial cells themselves. The infertility that is often associated with endometriosis is due, at least in part, to alterations in gene expression in the eutopic endometrium. These altered patterns of gene expression result in an endometrial environment that is not receptive to the implanting embryo and cannot sustain its development. We have shown that a glycosylated, trans-membrane protein called Extra-Cellular Matrix Metalloproteinase Inducer (EMMPRIN) is expressed in both the human and mouse uterus and regulates production of metalloproteinases by uterine stromal cells. EMMPRIN expression is upregulated in eutopic as well as ectopic endometrium of women and baboons with endometriosis. Using a mouse EMMPRIN knockout model we have shown that in mice lacking EMMPRIN expression, uterine stromal cells experience premature decidualization in response to oil injection and are infertile. Treatment of cultured uterine stromal cells with EMMPRIN inhibits expression of decidualization markers such as alkaline phosphatase-2 and induces expression of several cytokines and chemokines by these cells. Thus it appears that EMMPRIN is a multi-functional regulator of endometrial remodeling. Our specific aims are; #1: To determine how secretion of full-length, soluble EMMPRIN by uterine epithelial cells is regulated and how EMMPRIN regulates production of cytokines, chemokines and angiogenic factors by uterine stromal cells. #2: To determine how EMMPRIN regulates proliferation and decidualization of uterine stromal cells and to clarify the intra-cellular signaling pathway used by EMMPRIN in these cells. #3: To determine the effects of EMMPRIN on epithelial-to-mesenchymal transition of mesothelial cells. The proposed studies will clarify the role of EMMPRIN in invasion of endometrial fragments through the mesothelium leading to establishment of endometriotic lesions. They will also help to explain why aberrant expression of EMMPRIN in eutopic endometrium could result in failure of implantation.