Hyaluronan/CD44 and the Early Endometriotic Lesion

透明质酸/CD44与早期子宫内膜异位病变

• 批准号: 6605970
• 负责人: ROBERT S SCHENKEN
• 金额: $ 28.78万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6605970
• 关键词: CD44 molecule; SDS polyacrylamide gel electrophoresis; cell membrane; chemical binding; clinical research; endometriosis; endometrium; female; flow cytometry; glycosylation; human subject; hyaluronate; immunocytochemistry; immunofluorescence technique; immunoprecipitation; molecular pathology; monoclonal antibody; mucopolysaccharides; polymerase chain reaction; radiotracer; tissue /cell culture; women's health

DESCRIPTION (provided by applicant): Endometriosis is a common gynecologic disease affecting up to 10% of reproductive-age women. Despite this high prevalence and the severe symptoms associated with the disease, little is known about the pathogenesis of endometriosis. One theory, known as Sampson's theory, proposes that fragments of menstrual endometrium pass retrograde through the fallopian tubes into the peritoneal cavity where they attach and grow on peritoneal surfaces. We recently developed a novel in vitro model of endometriosis using explants of human peritoneum or mesothelial cell monolayers and mechanically dispersed endometrial cells. Our studies demonstrate that endometrial fragments rapidly adhere to intact cultured peritoneal mesothelium. Both ESC and EEC adhere to peritoneal mesothelium within one hour of plating. Recent studies suggest that hyaluronan, a linear disaccharides polymer produced by mesothelium, and CD44, a multifunctional type 1 transmembrane glycoprotein that regulates cell-cell interactions, are involved in the binding of ovarian cancer and gastric cancer cells to mesothelium. Using our model, we demonstrated that hyaluronidase inhibits attachment of endometrial cells to mesothelial cells suggesting that hyaluronan/CD44 is also involved in the pathogenesis of endometriosis. A significant body of evidence using cell types other than endometrial suggests that the CD44 isoform expression, CD44 cell surface density, and CD44 glycosylation/glycosaminoglycanation pattern differentially affect a cells ability to adhere to hyaluronan. Our preliminary data demonstrate that endometrial epithelial cells from women with endometriosis have a greater ability to bind to mesothelial cells and that binding to mesothelial cells is dependent on the cell surface density of CD44. These observations coupled with the variable expression of CD44 isoforms in human endometrium lead us to hypothesize that the qualitative and quantitative expression of CD44 regulates the ability of endometrial cells to adhere to peritoneal mesothelium. The novel experiments described herein will characterize CD44 cell isoform expression, cell surface density and glycosylation/glycosaminoglycanation patterns in endometrial cells of women with and without endometriosis. This will enhance our understanding of the development of the early endometriotic lesion. The findings should enable us to predict a woman's risk of developing endometriosis based on endometrial cell CD44 characteristics and suggest new approaches to prevent the disease.

描述（由申请人提供）：子宫内膜异位症是一种常见的妇科疾病，影响高达 10% 的育龄妇女。尽管这种疾病的患病率很高且症状严重，但人们对子宫内膜异位症的发病机制知之甚少。一种称为桑普森理论的理论提出，月经子宫内膜碎片逆行通过输卵管进入腹膜腔，在那里它们附着在腹膜表面并生长。我们最近使用人腹膜或间皮细胞单层和机械分散的子宫内膜细胞的外植体开发了一种新型子宫内膜异位症体外模型。我们的研究表明，子宫内膜碎片快速粘附到完整的培养腹膜间皮上。 ESC 和 EEC 在电镀后一小时内粘附到腹膜间皮上。最近的研究表明，透明质酸（一种由间皮产生的线性二糖聚合物）和 CD44（一种调节细胞间相互作用的多功能 1 型跨膜糖蛋白）参与卵巢癌和胃癌细胞与间皮的结合。使用我们的模型，我们证明透明质酸酶抑制子宫内膜细胞与间皮细胞的附着，表明透明质酸/CD44也参与子宫内膜异位症的发病机制。使用子宫内膜以外的细胞类型的大量证据表明，CD44同种型表达、CD44细胞表面密度和CD44糖基化/糖胺聚糖化模式对细胞粘附透明质酸的能力有不同影响。我们的初步数据表明，患有子宫内膜异位症的女性的子宫内膜上皮细胞具有更强的与间皮细胞结合的能力，并且与间皮细胞的结合取决于CD44的细胞表面密度。这些观察结果加上人子宫内膜中 CD44 同工型的可变表达，使我们推测 CD44 的定性和定量表达调节子宫内膜细胞粘附腹膜间皮的能力。本文描述的新颖实验将表征患有和不患有子宫内膜异位症的女性的子宫内膜细胞中的CD44+细胞亚型表达、细胞表面密度和糖基化/糖胺聚糖化模式。这将增强我们对早期子宫内膜异位病变发展的了解。这些发现应该使我们能够根据子宫内膜细胞 CD44 特征预测女性患子宫内膜异位症的风险，并提出预防该疾病的新方法。