Epithelial-Dominant Cell-Cell Communication and Endometriosis

妇女暴露于雌激素是导致子宫内膜异位症的主要内分泌危险因素，而孕期暴露于黄体酮则是该疾病的负面危险因素。然而，最近的证据表明，子宫内膜对孕激素的敏感性降低可能是整个疾病过程中的一个潜在的重要因素。为了明确子宫内膜对孕酮的反应性降低对子宫内膜异位症基本病理生理学的影响，我们重点研究了孕酮未能下调基质金属蛋白酶的表达。 (基质金属蛋白酶)系统的分泌成熟。建立异位子宫内膜生长所需的侵袭性事件涉及腹膜腔内细胞外基质的分解。在子宫内膜异位症的人/裸鼠嵌合模型中，孕酮未能下调子宫内膜关键基质金属蛋白酶的表达，增加了其组织的侵袭能力。我们假设，在患有子宫内膜异位症的女性中，黄体酮反应性降低会损害在位内膜内分泌成熟期间的细胞间通讯。黄体酮反应性的降低特别干扰了关键的转化生长因子-B(TGF-B)信号蛋白的表达，导致了上皮主导的细胞-细胞交流模式。上皮优势细胞-细胞通讯作用于增加基质金属蛋白酶的表达，促进子宫内膜碎片迅速侵入腹膜表面，形成血管，从而形成子宫内膜异位症。为了验证我们的假设，我们提出了三个特定的目标：1)确定间质细胞PR同型表达的中断和/或转化生长因子-β信号是否与孕酮未能下调子宫内膜异位症患者在位内膜中的基质金属蛋白酶-3和基质金属蛋白酶-7的表达有关，以及确定无论是否使用孕激素治疗，异位病变的手术减少是否能恢复正常的基质金属蛋白酶调节2)以确定在子宫内膜异位症患者体内孕酮敏感性是否降低。 子宫内膜异位症患者的子宫内膜在间质蜕膜化过程中对维甲酸的合成有负面影响3)为了确定在体外和体内侵袭性建立实验性子宫内膜异位症期间上皮-主导细胞-细胞通讯的功能影响。

A woman's exposure to estrogen represents her principal endocrine risk factor for developing endometriosis while exposure to progesterone during pregnancy represents a negative risk factor for this disease. However, recent evidence suggests that reduced endometrial sensitivity to progesterone may represent a potentially important element in the overall disease process. In an attempt to identify the consequences of reduced endometrial responsiveness to progesterone on the basic pathophysiology of endometriosis, we have focused on the failure of progesterone to down-regulate the expression of the matrix metalloproteinase (MMP) system during secretory maturation. The invasive events required for the establishment of ectopic endometrial growth involves the breakdown of extracellular matrix within the peritoneal cavity. The failure of progesteone to down-regulate endometrial expression of key MMPs in endometriosis patients increases the invasive capacity of their tissue in a chimeric human/nude mouse model of endometriosis. We hypothesize that, in women with endometriosis, reduced progesterone responsiveness compromises cell-cell communication during secretory maturation within the eutopic endometrium. Reduced progesterone responsiveness specifically disrupts the expression of key transforming growth factor-B (TGF-B) signaling proteins leading to an epithelial-dominant pattern of cell-cell communication. Epithelialdominant cell-cell communication acts to increase MMP expression and promote the ability of endometrial fragments to rapidly invade the peritoneal surface, acquire a vasculature and establish the disease endometriosis. To test our hypothesis, we propose three Specific Aims: 1) to determine whether disruption of PR isotype expression in stromal cells and/or TGF-B signaling is linked to .the failure of progesterone to down-regulate MMP-3 and MMP-7 expression in the eutopic endometium of women with endometriosis and to determine if surgical reduction of ectopic disease with or without progesterone therapy restores normal MMP regulation 2) to determine whether reduced progesterone sensitivity in the endometrium of women with endometriosis negatively affects the synthesis of retinoic acid during stromal decidualization 3) to determine the functional impact of epithelial-dominant cell-cell communication in vitro and during the invasive establishment of experimental endometriosis in vivo.