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

描述(申请人提供)：子宫内膜异位症是一种常见的妇科疾病，影响高达10%的育龄妇女。尽管这种疾病的发病率很高，症状也很严重，但对子宫内膜异位症的发病机制知之甚少。一种被称为桑普森理论的理论认为，月经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。我们已经建立了早期子宫内膜异位病变的新的体外和体内(小鼠)模型。我们的模型表明，子宫内膜碎片迅速附着在完整的腹膜间皮细胞上，然后迅速侵入腹膜间皮下细胞外基质(ECM)。集落刺激因子-1(CSF-1)最初被认为是一种造血生长因子，现已被证明在非造血细胞中具有重要的功能。CSF-1与其受体c-FMS的相互作用与多种肿瘤的生长、侵袭和转移密切相关。CSF-1和c-FMS由子宫内膜间质和上皮细胞(ESCs和EECs)以及腹膜间皮细胞(PMC)表达。我们的初步数据显示：(1)子宫内膜细胞与PMC共培养增加了子宫内膜细胞和PMC表达CSF-1和c-FMS，(2)CSF-1与c-FMS相互作用促进了子宫内膜的增殖和迁移，(3)子宫内膜细胞分泌CSF-1减少，导致细胞增殖和迁移减少，并改变了与侵袭、转移和细胞信号有关的基因的转录，(4)针对c-FMS信号转导的药物，在体外和体内子宫内膜异位症模型中，导致子宫内膜异位病变的形成。综上所述，我们的初步观察导致我们假设，CSF-1/c-FMS信号通过增加子宫内膜-PMC附着、子宫内膜跨间皮迁移以及间皮下ECM中子宫内膜组织的生长来参与子宫内膜异位症的发病机制。在拟议的研究中，我们将使用我们的体外和体内子宫内膜异位症模型：(1)评估子宫内膜-PMC共培养对子宫内膜和非子宫内膜异位症患者子宫内膜和PMC表达CSF-1和c-FMS的影响；(2)评估CSF-1刺激对子宫内膜附着、侵袭和腹膜生长的影响，并评估CSF-1/c-FMS介导的可能促进子宫内膜异位症的作用机制；(3)显示干扰CSF-1/c-FMS信号转导降低子宫内膜附着、侵袭和腹膜生长的比率，以及(4)评估目前可用的可降低c-FMS信号转导的药物作为治疗子宫内膜异位症的潜在方法。这些研究旨在提高我们对子宫内膜异位症发病机制的认识，增加我们对CSF-1/c-FMS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。 公共卫生相关声明：子宫内膜异位症是一种子宫内膜细胞(即子宫腔内的组织)在腹膜内生长的疾病。这是一种常见的妇科疾病，影响高达10%的育龄妇女。集落刺激因子-1(CSF-1)最初被描述为一种血细胞生长因子，已被证明在其他类型的细胞中具有重要功能，包括子宫内膜细胞和腹膜细胞。这些研究旨在提高我们对子宫内膜异位症发病机制的认识，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。

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.