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

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。尽管发病率高，症状严重，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，月经期子宫内膜的碎片通过输卵管逆行进入腹膜腔，在腹膜表面附着并生长。我们已经开发了新的体外和体内（小鼠）模型的早期子宫内膜异位症病变。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上，然后迅速侵入间皮下细胞外基质（ECM）。集落刺激因子-1 （CSF-1）最初被描述为一种造血生长因子，已被证明在非造血细胞中具有重要功能。CSF-1与其受体c-fms的相互作用与几种癌症的生长、侵袭和转移有关。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（PMCs）表达。我们的初步数据表明：(1)子宫内膜细胞和PMCs共培养增加了子宫内膜细胞和PMCs中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)子宫内膜细胞中CSF-1的产生减少导致细胞增殖和迁移减少，以及与侵袭、转移和细胞信号传导相关的基因转录改变；(4)针对c-fms信号传导的药物。在体外和体内子宫内膜异位症模型中导致子宫内膜异位症病变形成率降低。总的来说，我们的初步观察使我们假设CSF-1/c-fms信号通过增加子宫内膜- pmc附着率、子宫内膜经间皮迁移率和间皮下ECM中子宫内膜组织的生长率，参与了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共培养对有、无子宫内膜异位症患者子宫内膜和PMC中CSF-1和c-fms表达的影响；(2)评估刺激CSF-1对子宫内膜附着、侵袭和腹膜生长的影响，并评估CSF-1/c-fms介导的可能导致子宫内膜异位症的作用机制；(3)证明干扰CSF-1/c-fms信号可降低子宫内膜附着率。腹膜的侵袭和生长，以及(4)评估目前可用的可能降低c-fms信号的药物作为子宫内膜异位症的潜在治疗方法。本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，并为预防和治疗这种疾病提供创新的方法。

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.