Epithelial-Dominant Cell-Cell Communication and Endometriosis

上皮优势细胞间通讯和子宫内膜异位症

基本信息

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
项目类别：
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

项目摘要

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.

女性接触雌激素是患子宫内膜异位症的主要内分泌风险因素，而怀孕期间接触孕激素则是该疾病的负面风险因素。然而，最近的证据表明，子宫内膜对黄体酮敏感性的降低可能是整个疾病过程中潜在的重要因素。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学的影响，我们重点关注孕酮未能下调基质金属蛋白酶的表达 (MMP) 系统在分泌成熟过程中。建立异位子宫内膜生长所需的侵入事件涉及腹膜腔内细胞外基质的分解。在子宫内膜异位症嵌合人/裸鼠模型中，孕酮未能下调子宫内膜异位症患者中关键 MMP 的子宫内膜表达，从而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子宫内膜分泌成熟过程中的细胞间通讯。黄体酮反应性降低会特异性破坏关键转化生长因子 B (TGF-B) 信号蛋白的表达，从而导致细胞间通讯的上皮主导模式。上皮优势细胞间通讯可增加 MMP 表达并促进子宫内膜碎片快速侵入腹膜表面、获得脉管系统并形成子宫内膜异位症的能力。为了检验我们的假设，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-B 信号传导的破坏是否与孕酮未能下调 MMP-3 和 MMP-7 有关2) 确定患有子宫内膜异位症的女性在位子宫内膜中的表达，并确定手术减少异位病变（无论有或没有黄体酮治疗）是否恢复正常的 MMP 调节孕激素敏感性患有子宫内膜异位症的女性子宫内膜在基质蜕膜化过程中对视黄酸的合成产生负面影响3)以确定体外上皮优势细胞间通讯的功能影响以及体内实验性子宫内膜异位症侵入性建立过程中的功能影响。