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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(申请人提供)：早在1927年，Sampson就提出了子宫内膜异位症的理论，认为子宫内膜异位症的发生是通过逆行月经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，本实验室已证实，在子宫内膜异位症的子宫内膜中，炎性样微环境改变了孕激素受体(PR-A和PR-B)的表达比例，扰乱了孕酮上调转化生长因子(TGF-β)表达的能力，下调了细胞特异性基质金属蛋白酶(MMPs)的表达。许多研究人员现在怀疑，子宫内膜异位症的发生是孕激素未能控制免疫细胞在月经前迁移到子宫内膜的促炎活性的可预见后果。在正常子宫内膜中，衰变加速因子(CD55)在孕酮的作用下上调，提示这种补体保护蛋白在妊娠准备过程中可能在控制免疫细胞的行为方面发挥关键作用。尽管上皮CD55表达降低与子宫内膜异位症发生发展的关系尚不清楚，但已知在炎症过程中，转化生长因子β和CD55都会影响中性粒细胞(PMN)的激活和功能。中性粒细胞是早期炎症的关键触发细胞，在月经期间可显著增加基质金属蛋白酶的表达。我们已经注意到在我们使用免疫缺陷小鼠建立的子宫内膜异位症嵌合模型中，中性粒细胞在人类细胞生长的异位部位迅速积累。在这一应用中，我们认为，减少PR-B在子宫内膜异位症患者子宫内膜间质细胞中的表达，将抑制体内、体外和实验性小鼠子宫内膜异位内膜细胞生长的孕酮依赖性转化生长因子-β2和CD55的表达。我们还预测，这些因子的表达变化将影响中性粒细胞的激活状态，这些中性粒细胞迁移到人子宫内膜细胞和小鼠组织生长的异位部位。我们的具体目标是：1)检测子宫内膜对孕酮的反应性降低是否影响子宫内膜异位症患者在位内膜上皮细胞在体内和体外对CD55的表达；2)利用建立的体外和体内共培养模型来检测对孕酮的敏感性降低是否影响从子宫内膜异位症患者获得的子宫内膜间质细胞介导相邻上皮细胞CD55表达的能力；以及3)利用新建立的体内模型来检测RAG2中转化生长因子-β2和CD55的表达是否与PMN在人类细胞和组织生长的异位部位的募集和功能有关？(C)小鼠。