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

基本信息

批准号：
8054242
负责人：
KEVIN G OSTEEN
金额：
$ 49.53万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8054242
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 Neutrophil Activation Neutrophil Infiltration Nude Mice Ovarian Patients Pattern Peritoneal Peritoneum Phase Play Population Pregnancy Preparation 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 repaired response

项目摘要

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（由适用提供）：早在1927年，桑普森理论上就可以通过逆行月经将子宫内膜组织机械转移到腹膜，这是大多数女性发生的过程。 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）表达。现在，许多研究人员怀疑子宫内膜异位症是孕酮无法控制免疫细胞的促炎活性的可预测结果，这些免疫细胞在月经之前迁移到子宫内膜。在正常子宫内膜中，衰减加速因子（CD55）响应孕激素而进行更新，这表明这种补体保护蛋白在控制怀孕期间免疫细胞的行为中可能起关键作用。尽管尚不清楚上皮CD55表达与子宫内膜异位症的发展的关系尚不清楚，但众所周知，TGF- - 和CD55都会影响炎症期间多形核中性粒细胞（PMN）的激活和功能。 PMN是早期炎症期间的关键触发细胞，并且在月经期间可以显着增加MMP的表达。我们已经注意到使用免疫缺陷小鼠的子宫内膜异位症嵌合模型，PMN在人类细胞生长模型中的生态生长的生长迅速积累。在此应用中，我们提出，在体内，体外和子宫内膜细胞生长的子宫内膜细胞生长的子宫内膜依赖性表达中降低了子宫内膜异位症患者子宫内膜基质细胞的表达。我们还预测，这些因素的表达改变将影响PMN的活化状态，这些PMN迁移到小鼠人子宫内膜细胞和组织生长中的edopic位点。我们的具体目的是：1） - 检查子宫内膜细胞中上皮细胞对子宫内膜异位症的层状子宫内膜中上皮细胞的体内和体外表达的子宫内膜反应能力是否会影响CD55的体外表达； 2） - 在体外和体内共培养模型中使用降低对谚语的敏感性是否会影响从子宫内膜异位症患者获得的子宫内膜基质细胞的能力，以介导相邻上皮细胞中CD55表达的CD55表达以及3） - 以及3） - 以pm pm and pm pm pm pm and pm pm pm pm corteruit and contruit cortruit cormatiuit dectruit cormatiuit dect cortruit是否具有tg55和cd55的表达。255555。 RAG2中人类细胞和组织生长的生态部位？（c）小鼠。