CSF-1 and c-fms and the Early Endometriotic Lesion

CSF-1和c-fms与早期子宫内膜异位病变

• 批准号: 7569289
• 负责人: RAJESHWAR R TEKMAL
• 金额: $ 32.6万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569289
• 关键词: Abdominal Cavity; Affect; Age; Antibodies; Biological Assay; Blood Cells; Cell Line; Cell Proliferation; Cell-Matrix Junction; Cells; Coculture Techniques; Data; Disease; Endometrial; Endometrial Stromal Cell; Endometrium; Epithelial Cells; Extracellular Matrix; Female Genital Diseases; Flow Cytometry; Fluorescence; Genetic Transcription; Goals; Greater sac of peritoneum; Growth; Growth Factor; Growth and Development function; Hematopoietic; Hematopoietic Cell Growth Factors; High Prevalence; Hour; Human; Imatinib; Immunocompromised Host; In Vitro; Injection of therapeutic agent; Interruption; Invaded; Knock-out; Knockout Mice; Knowledge; Label; Lead; Lesion; Little' s Disease; Macrophage Colony-Stimulating Factor; Malignant Female Reproductive System Neoplasm; Mammalian Oviducts; Mediating; Mesothelium; Metastatic Neoplasm to the Breast; Methods; Modeling; Molecular; Mus; Neoplasm Metastasis; Nude Mice; Pathogenesis; Pathway interactions; Patients; Peritoneal; Peritoneal Mesothelial Cell; Peritoneum; Phase; Physiological; Production; Research; Research Design; Role; Signal Transduction; Signal Transduction Inhibitor; Small Interfering RNA; Surface; Symptoms; Techniques; Therapeutic Intervention; Tissues; Uterine cavity; Wild Type Mouse; Woman; c-fms Proto-Oncogenes; cancer type; cell type; endometriosis; improved; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; innovation; migration; monolayer; novel; novel strategies; prevent; public health relevance; receptor; reproductive; research study; theories; three-dimensional modeling

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 have developed novel in vitro and in vivo (murine) models of the early endometriotic lesion. Our models demonstrate that endometrial fragments rapidly adhere to intact peritoneal mesothelium then promptly invade into the submesothelial extracellular matrix (ECM). Colony stimulating factor-1 (CSF-1), initially described as a hematopoietic growth factor, has been shown to have important functions in non-hematopoietic cells. CSF-1 interaction with its receptor, c-fms, has been implicated in the growth, invasion, and metastasis of several types of cancer. CSF-1 and c-fms are expressed by endometrial stromal and epithelial cells (ESCs and EECs), and peritoneal mesothelial cells (PMCs). Our preliminary data demonstrate that: (1) co-culture of endometrial cells and PMCs increases expression of CSF-1 and c-fms by endometrial cells and PMCs, (2) CSF-1 interaction with c-fms increases endometrial proliferation and migration, (3) decreased production of CSF-1 by endometrial cells leads to decreased cell proliferation and migration as well as altered transcription of genes implicated in invasion, metastasis, and cell signaling, and (4) pharmacologic agents, targeted against c-fms signaling, lead to a decreased rate of endometriotic lesion formation in an in vitro and in vivo model of endometriosis. Collectively, our preliminary observations lead us to hypothesize that CSF-1/c-fms signaling contributes to the pathogenesis of endometriosis by increasing the rate of: endometrial-PMC attachment, transmesothelial migration by endometrium, and growth of endometrial tissue in the submesothelial ECM. In the proposed studies we will use our in vitro and in vivo models of endometriosis to: (1) evaluate the effect of endometrial- PMC co-culture on the endometrial and PMC expression of CSF-1 and c-fms from patients with and without endometriosis, (2) evaluate the effect of CSF-1 stimulation on endometrial attachment, invasion and growth in the peritoneum, and evaluate the mechanisms involved in CSF-1/c-fms mediated actions that may contribute to endometriosis, (3) demonstrate that interference with CSF-1/c-fms signaling decreases the rate of endometrial attachment, invasion and growth in the peritoneum, and (4) evaluate currently available pharmacologic agents that may decrease c-fms signaling as a potential treatment for endometriosis. The proposed studies are designed to improve our knowledge regarding the pathogenesis of the endometriotic lesion, increase our understanding of the contribution of CSF-1/c-fms signaling in endometriosis, and lead to innovative methods to prevent and treat this disease. Public Health Relevance Statement: Endometriosis is a disease in which there is growth of endometrial cells (i.e. the tissue that lines the uterine cavity) in the abdominal cavity. It is a common gynecologic disease affecting up to 10% of reproductive-age women. Colony stimulating factor-1 (CSF-1), initially described as a growth factor for blood cells, has been shown to have important functions in other cells types including endometrial cells and cells that line the abdominal cavity. The proposed studies are designed to improve our knowledge regarding the pathogenesis of the endometriotic lesion, increase our understanding of the contribution of CSF-1 signaling in endometriosis, and lead to innovative methods to prevent and treat this 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，影响多达10%的育龄妇女。尽管这种高患病率和严重的症状与疾病有关，很少有人知道子宫内膜异位症的发病机制。一种理论，称为桑普森理论，提出月经期子宫内膜的碎片通过输卵管逆行进入腹膜腔，在那里它们附着并生长在腹膜表面上。我们已经开发了新的体外和体内（小鼠）模型的早期乳腺癌病变。我们的模型表明，子宫内膜碎片迅速粘附到完整的腹膜间皮，然后迅速侵入间皮下细胞外基质（ECM）。集落刺激因子-1（CSF-1）最初被描述为造血生长因子，已显示在非造血细胞中具有重要功能。CSF-1与其受体c-fms的相互作用涉及几种类型癌症的生长、侵袭和转移。CSF-I和c-fms由子宫内膜基质细胞和上皮细胞（ESC和EEC）以及腹膜间皮细胞（PMC）表达。我们的初步数据表明：（1）子宫内膜细胞和PMC的共培养增加了子宫内膜细胞和PMC的CSF-1和c-fms的表达，（2）CSF-1与c-fms的相互作用增加了子宫内膜的增殖和迁移，（3）子宫内膜细胞的CSF-1产生减少导致细胞增殖和迁移减少以及涉及侵袭、转移、和细胞信号传导;和（4）靶向C-FMS信号传导的药理学试剂，导致子宫内膜异位症的体外和体内模型中子宫内膜异位性损伤形成的速率降低。总的来说，我们的初步观察使我们假设CSF-1/c-fms信号传导通过增加以下速率促进子宫内膜异位症的发病：子宫内膜-PMC附着、子宫内膜跨间皮迁移和子宫内膜组织在间皮下ECM中的生长。在拟议的研究中，我们将使用我们的子宫内膜异位症体外和体内模型：（1）评价子宫内膜- PMC共培养对来自患有和不患有子宫内膜异位症的患者的子宫内膜和PMC的CSF-1和c-fms表达的影响，（2）评价CSF-1刺激对子宫内膜附着、侵袭和在腹膜中生长的影响，并评估可能导致子宫内膜异位症的CSF-1/c-fms介导的作用所涉及的机制，（3）证明干扰CSF-1/c-fms信号传导降低了子宫内膜附着、侵袭和在腹膜中生长的速率，和（4）评价目前可用的可降低c-FMS信号传导的药理学试剂作为子宫内膜异位症的潜在治疗。拟议的研究旨在提高我们对子宫内膜异位症病变发病机制的认识，增加我们对CSF-1/c-fms信号传导在子宫内膜异位症中的贡献的理解，并导致预防和治疗这种疾病的创新方法。 公共卫生相关性声明：子宫内膜异位症是一种子宫内膜细胞（即衬在子宫腔上的组织）在腹腔中生长的疾病。它是一种常见的妇科疾病，影响多达10%的育龄妇女。集落刺激因子-1（CSF-1）最初被描述为血细胞的生长因子，已被证明在其他细胞类型中具有重要功能，包括子宫内膜细胞和腹腔细胞。拟议的研究旨在提高我们对子宫内膜异位症病变发病机制的认识，增加我们对CSF-1信号在子宫内膜异位症中的作用的理解，并导致预防和治疗这种疾病的创新方法。