Epithelial-Dominant Cell-Cell Communication and Endometriosis

上皮优势细胞间通讯和子宫内膜异位症

• 批准号: 8256514
• 负责人: KEVIN G OSTEEN
• 金额: $ 19.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256514
• 关键词: Affect; All-Trans-Retinol; Behavior; Biology; Cell Communication; Cells; Coculture Techniques; Complement Factor B; Decidual Cell Reactions; Defect; Development; Disease; Endocrine; Endometrial; Endometrial Stromal Cell; Endometrium; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; Estrogens; Estrus; Event; Exhibits; Experimental Models; Exposure to; Extracellular Matrix; Extracellular Matrix Degradation; Failure; Functional disorder; Greater sac of peritoneum; Growth; Human; Immune; Implant; In Vitro; Indium; Inflammatory; Invaded; Laboratories; Lesion; Link; Matrilysin; Matrix Metalloproteinases; Mediating; Menstrual cycle; Menstruation; Modeling; Nude Mice; Nutrient; Olives - dietary; Operative Surgical Procedures; Patients; Pattern; Peritoneal; Phase; Pregnancy; Preparation; Process; Production; Progesterone; Progestin Therapy; Progestins; Reflux; Regulation; Research; Risk Factors; Rodent; Role; Secondary to; Signal Transduction; Signaling Protein; Site; Stromal Cells; Stromelysin 1; Surface; System; Testing; Tissues; Transforming Growth Factors; Tretinoin; Vascularization; Woman; base; cell type; cytokine; endometriosis; improved; in vivo; mouse model; novel; prevent; progesterone receptor B; wound

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.

女性暴露于雌激素是其发生子宫内膜异位症的主要内分泌危险因素，而妊娠期间暴露于孕酮则是这种疾病的负危险因素。 然而，最近的证据表明，子宫内膜对孕酮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。为了确定子宫内膜对孕酮反应性降低对子宫内膜异位症基本病理生理的影响，我们集中研究了孕酮不能下调基质金属蛋白酶的表达 (MMP)系统在分泌成熟。建立异位子宫内膜生长所需的侵入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嵌合人/裸鼠模型中，雌激素不能下调子宫内膜关键MMP的表达，增加了其组织的侵袭能力。我们推测，在子宫内膜异位症患者中，孕酮反应性降低会影响在位子宫内膜分泌成熟过程中的细胞间通讯。降低孕酮反应性特异性地破坏关键转化生长因子-B（TGF-β）信号传导蛋白的表达，导致上皮主导的细胞-细胞通讯模式。上皮优势细胞间通讯可增加MMP的表达，促进子宫内膜碎片迅速侵入腹膜表面，获得血管，形成子宫内膜异位症。为了验证我们的假设，我们提出了三个具体目标：1）确定基质细胞中PR同种型表达和/或TGF-β信号传导的破坏是否与孕酮不能下调患有子宫内膜异位症的妇女的在位子宫内膜中MMP-3和MMP-7表达有关，并确定在有或没有孕酮治疗的情况下手术减少异位疾病是否恢复正常的MMP调节以确定是否降低孕酮敏感性， 患有子宫内膜异位症的妇女的子宫内膜在间质蜕膜化过程中对视黄酸的合成产生负面影响3）以确定体外和体内实验性子宫内膜异位症的侵入性建立过程中上皮优势细胞-细胞通讯的功能影响。