Loss of Complement-Protective CD55 Expression in Endometriosis

子宫内膜异位症中补体保护性 CD55 表达缺失

• 批准号: 7416834
• 负责人: KEVIN G OSTEEN
• 金额: $ 46.24万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7416834
• 关键词: Adoptive Transfer; Affect; Attention; Behavior; Behavior Control; Biological; CD46 Antigen; CD55 Antigens; Cell physiology; Cells; Chronic; Coculture Techniques; Communication; Complement; Condition; Defect; Development; Disease; Disease Progression; Effectiveness; Elements; Endocrine system; Endoglin; Endometrial; Endometrial Stromal Cell; Endometrium; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; Epithelium; Event; Exhibits; Experimental Models; Exposure to; Failure; Functional disorder; Gene Proteins; Growth; Human; Hypoxia; Immune; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Injury; Interleukin-1; Invaded; Kidney; Laboratories; Link; Luteal Phase; Maternal-Fetal Exchange; Matrilysin; Matrix Metalloproteinases; Mechanics; Mediating; Menstruation; Modeling; Mus; Natural Immunity; Nude Mice; Numbers; Ovarian; Patients; Pattern; Peritoneal; Peritoneum; Phase; Play; Population; Pregnancy; Preparation; Principal Investigator; Process; Progesterone; Progesterone Receptors; Progestin Therapy; Proteins; Regulation; Relative (related person); Reproduction; Research Personnel; Retrograde Menstruation; Risk; Role; Seminal; Series; Signal Transduction; Site; Steroids; Stromal Cells; System; Time; Tissues; Transcriptional Activation; Transforming Growth Factors; Up-Regulation; Uterus; Vascular Endothelial Growth Factors; Woman; angiogenesis; capsule; cell growth; cell type; cytokine; cytotrophoblast; endometriosis; granulocyte; human tissue; implantation; in vivo; in vivo Model; injured; killings; migration; neutrophil; pathogen; prevent; progesterone receptor A; progesterone receptor B; programs; repaired; response

DESCRIPTION (provided by applicant): As early as 1927, Sampson theorized that endometriosis occurs as a consequence of the mechanical transfer of endometrial tissue to the peritoneum via retrograde menstruation, a process that occurs in most women. Using both in vivo observations and in vitro studies, our laboratory has demonstrated that, in the endometrium of endometriosis, an inflammatory-like microenvironment alters the expression ratio of progesterone receptors (PR-A and PR-B), disrupts the ability of progesterone to up-regulate transforming growth factor ¿ (TGF-¿) expression and down-regulates cell-specific matrix metalloproteinase (MMP) expression. Many investigators now suspect that endometriosis occurs as a predictable consequence of the failure of progesterone to control the proinflammatory activity of immune cells that migrate into the endometrium prior to menstruation. In the normal endometrium, decay accelerating factor (CD55) is upregulated in response to progesterone, suggesting that this complement protective protein may play a critical role in controlling the behavior of immune cells during preparation for pregnancy. Although the relationship of reduced epithelial CD55 expression to the development of endometriosis is unknown, both TGF-¿ and CD55 are known to impact the activation and function of polymorphonuclear neutrophils (PMNs) during inflammation. PMNs are key trigger cells during early inflammation and can significantly increase MMP expression during menstruation. We have noted the rapid accumulation of PMNs at ectopic sites of human cell growth in our chimeric models of endometriosis using immune deficient mice. In this application, we propose that reduced expression of PR-B in endometrial stromal cells of endometriosis patients will inhibit progesterone-dependent expression of TGF-¿2 and CD55 in vivo, in vitro and at ectopic sites of endometrial cell growth in experimental murine models of endometriosis. We also predict that altered expression of these factors will affect the activated state of PMNs that migrate into ectopic sites of human endometrial cell and tissue growth in mice. Our specific aims are: 1)- to examine whether reduced endometrial responsiveness to progesterone affects the in vivo and in vitro expression of CD55 by epithelial cells in the eutopic endometrium of women with endometriosis; 2)- to utilize established in vitro and in vivo co-culture models to examine whether reduced sensitivity to progesterone affects the ability of endometrial stromal cells acquired from endometriosis patients to mediate CD55 expression in adjacent epithelial cells, and 3)- to utilize newly established in vivo models to examine whether the expression of TGF-¿2 and CD55 correlates with PMN recruitment and function at ectopic sites of human cell and tissue growth in RAG2? (c) mice.

描述（由申请人提供）：早在 1927 年，桑普森就通过体内观察和体外观察推测，子宫内膜异位症是子宫内膜组织通过逆行月经机械转移到腹膜的结果，这一过程发生在大多数女性身上。我们实验室的研究表明，在子宫内膜异位症的子宫内膜中，炎症样微环境改变了孕激素受体（PR-A和 PR-B），破坏黄体酮上调转化生长因子的能力 ¿ (TGF-¿) 表达并下调细胞特异性基质金属蛋白酶 (MMP) 表达，许多研究人员现在怀疑，子宫内膜异位症的发生是孕酮未能控制先前迁移到子宫内膜的免疫细胞的促炎活性的可预测结果。在正常子宫内膜中，衰变加速因子（CD55）响应黄体酮而上调，表明这种补体保护蛋白可能在控制行为中发挥关键作用。尽管上皮 CD55 表达减少与子宫内膜异位症发展的关系尚不清楚，但 TGF-¿已知 CD55 和 CD55 在炎症过程中影响多形核中性粒细胞 (PMN) 的激活和功能，PMN 是早期炎症过程中的关键触发细胞，并且可以在月经期间显着增加 MMP 的表达。使用免疫缺陷小鼠在我们的子宫内膜异位症嵌合模型中生长。在本申请中，我们提出子宫内膜异位症患者的子宫内膜基质细胞中 PR-B 的表达减少。抑制 TGF-¿ 的孕酮依赖性表达我们还预测，这些因子的表达改变将影响迁移到人类子宫内膜细胞和组织异位部位的 PMN 的激活状态。我们的具体目标是：1)-检查子宫内膜对孕酮的反应性降低是否会影响子宫内膜上皮细胞的 CD55 表达。子宫内膜异位症患者的在位子宫内膜；2)-利用已建立的体外和体内共培养模型来检查对孕酮敏感性的降低是否影响从子宫内膜异位症患者获得的子宫内膜基质细胞介导邻近上皮细胞中 CD55 表达的能力，以及3)-利用新建立的体内模型来检测TGF-¿的表达是否2 和 CD55 与 RAG2? (c) 小鼠中人类细胞和组织生长异位位点的 PMN 募集和功能相关。