EMMPRIN Regulates Tissue Remodeling in the Endometrium

子宫内膜异位症的定义是异位部位的子宫内膜腺和间质，最常见的是 在盆腔内的腹膜上。据估计，子宫内膜异位症的发病率在30- 60%的女性患有盆腔疼痛和不孕不育，相关的医疗保健费用是巨大的。 异位子宫内膜碎片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本身在局部分泌的因子。这就是不孕不育 通常与子宫内膜异位症有关，至少部分是由于在位基因表达的改变。 子宫内膜。这些基因表达模式的改变导致子宫内膜环境不同于 接受植入胚胎，不能维持其发育。我们已经证明了糖基化的， 一种称为细胞外基质金属蛋白酶诱导物(EMMPRIN)的跨膜蛋白在 在人类和小鼠子宫中均有表达，并调节子宫基质细胞金属蛋白酶的产生。 EMMPRIN在子宫内膜异位内膜和异位内膜中的表达 子宫内膜异位症。使用小鼠EMMPRIN基因敲除模型，我们已经表明在缺乏EMMPRIN的小鼠中 子宫基质细胞对注射油的反应经历了过早的蜕膜化，并 不孕不育。EMMPRIN处理培养的子宫基质细胞抑制蜕膜化的表达 碱性磷酸酶-2等标志物诱导多种细胞因子和趋化因子的表达 这些细胞。因此，EMMPRIN是子宫内膜重塑的多功能调节因子。我们的 具体目标是：#1：确定子宫上皮细胞如何分泌全长的、可溶的EMMPRIN 以及EMMPRIN如何通过以下途径调节细胞因子、趋化因子和血管生成因子的产生 子宫基质细胞。#2：确定EMMPRIN如何调节子宫的增殖和蜕膜化 并阐明EMMPRIN在这些细胞中使用的细胞内信号通路。 #3：确定EMMPRIN对间皮细胞上皮向间充质转化的影响。 拟议的研究将阐明EMMPRIN在子宫内膜碎片侵袭中的作用。 间皮导致子宫内膜异位病变的建立。它们还将有助于解释为什么异常 EMMPRIN在在位内膜中的表达可能导致着床失败。

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.