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: 7799132
• 负责人: KEVIN G OSTEEN
• 金额: $ 48.57万
• 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/7799132
• 关键词: Adoptive Transfer; Affect; Attention; Behavior; Behavior Control; Biological; CD46 Antigen; CD55 Antigens; Cell physiology; Cells; Chronic; Coculture Techniques; Communication; Complement; 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; 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; Transforming Growth Factors; Up-Regulation; Uterus; Vascular Endothelial Growth Factors; Woman; angiogenesis; capsule; cell growth; cell type; complement system; 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，Sampson就提出子宫内膜异位症的发生是由于月经逆行将子宫内膜组织机械转移到腹膜的结果，这一过程发生在大多数女性身上。通过体内观察和体外研究，我们的实验室已经证明，在子宫内膜异位症中，炎症样微环境改变了孕激素受体（PR-A和PR-B）的表达比例，破坏了孕激素上调转化生长因子（TGF-）表达和下调细胞特异性基质金属蛋白酶（MMP）表达的能力。许多研究者现在怀疑子宫内膜异位症的发生是由于黄体酮无法控制月经前移入子宫内膜的免疫细胞的促炎活性。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准备妊娠期间控制免疫细胞的行为中发挥关键作用。虽然上皮细胞CD55表达减少与子宫内膜异位症的关系尚不清楚，但已知TGF-¿和CD55在炎症期间都会影响多形核中性粒细胞（pmn）的激活和功能。pmn是早期炎症的关键触发细胞，可以显著增加月经期间MMP的表达。我们注意到，在使用免疫缺陷小鼠的子宫内膜异位症嵌合模型中，pmn在人类细胞生长的异位部位迅速积累。在本应用中，我们提出降低子宫内膜异位症患者子宫内膜基质细胞中PR-B的表达会抑制孕激素依赖性TGF-¿2和CD55在体内、体外以及实验性子宫内膜异位症小鼠模型中子宫内膜细胞生长异位部位的表达。我们还预测，这些因子表达的改变将影响迁移到人子宫内膜细胞异位的pmn的激活状态和小鼠的组织生长。我们的具体目的是：1)-检查子宫内膜对黄体酮反应性降低是否影响子宫内膜异位症女性异位子宫内膜上皮细胞在体内和体外CD55的表达；2)-利用已建立的体外和体内共培养模型，研究孕酮敏感性降低是否会影响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CD55表达的能力；3)-利用新建立的体内模型，研究TGF-¿2和CD55的表达是否与RAG2中人类细胞和组织生长异位部位的PMN募集和功能相关？(c)老鼠。