The Role of the Matrisome in Endometriosis Development

项目摘要/摘要： 子宫内膜异位症是一种因子宫内膜组织异常生长而引起的妇科疾病。 宫腔。这种疾病会导致慢性疼痛、伴随月经的极度疼痛和/或至少7.4%的不孕症 每年有一百万美国女性。每年的成本负担超过700亿美元，而且没有治愈或有效的方法 治疗方法是存在的。一种常见的治疗方法是抑制卵巢雌激素的产生，但一旦停止 70%的女性报告有症状性疾病。患有子宫内膜异位症的女性免疫细胞增加 在他们的腹膜腔内，往往有较高的自身免疫性疾病的发生率；然而，其发病机制 子宫内膜异位症的发病机制仍知之甚少。来自我们的子宫内膜异位症小鼠模型的数据，在该模型中，供体 子宫组织被自由分散到具有免疫能力的宿主的腹膜腔内，已经发现 子宫内膜异位症的发病依赖于免疫系统。这些数据来自我们的鼠标模型 与女性身上的变化有关。我们的长期目标是为 基于机制的预防、诊断和/或治疗子宫内膜异位症的策略。这项提案的目标是 探讨中性粒细胞和巨噬细胞介导的信号转导在子宫组织附着中的作用 子宫内膜异位症的免疫依赖期。因此，我们假设子宫细胞、中性粒细胞、 和MΦS在子宫内膜异位症患者体内分泌促进和支持的母体和母体相关因子 EMS损伤建立。以下目标旨在检验这一假设：目标1将确定 中性粒细胞数量及其分泌的信号分子在子宫内膜异位症中的作用 病变附着物。目标2将鉴定巨噬细胞群并表征如何分泌信号 分子对子宫内膜异位症病变的存活率有贡献。目标3将揭示导致 在体外和体内形成EMS病变的子宫组织。在成功完成这项拟议的研究后， 这一结果有望对理解子宫内膜异位症产生重要的积极影响。数据 将对以机制为基础的框架阐明子宫内膜异位症的发病机制做出实质性贡献 反过来，将为确定新疗法的开发目标提供新的机会。

PROJECT SUMMARY/ABSTRACT: Endometriosis is a gynecological disease resulting from abnormal growth of endometrial tissue outside the uterine cavity. This disease causes chronic pain, extreme pain with menstruation, and/or infertility in at least 7.4 million American women per year. The annual cost burden exceeds $70 billion and no cure or effective treatments exist. A common therapy is the suppression of ovarian estrogen production, but upon cessation of treatment >70% of women report symptomatic disease. Women with endometriosis have increased immune cells in their peritoneal cavity and often have higher incidences of autoimmune disorders; however, the pathogenesis of endometriosis remains poorly understood. Data from our mouse model of endometriosis, in which donor uterine tissue is freely dispersed into the peritoneal cavity of an immunocompetent host, has uncovered that initiation of endometriosis is dependent on the immune system. These data from our mouse model strongly correlate with alterations seen in women. Our long-term goal is to contribute toward the development of mechanism-based strategies to prevent, diagnose, and/or treat endometriosis. The objective in this proposal is to determine the role of neutrophil and macrophage mediated signaling on uterine tissue attachment during the immune-dependent phase of endometriosis. Therefore, we hypothesize the crosstalk among uterine cells, PMNs, and MΦs in women with EMS secrete matrisome and matrisome associated factors that promote and support EMS lesion establishment. The following aims are designed to test this hypothesis: Aim 1 will identify the neutrophil population and characterize how their secreted signaling molecules contribute to endometriosis lesion attachment. Aim 2 will identify the macrophage population and characterize how secreted signaling molecules contribute to endometriosis lesion survival. Aim 3 will uncover key matrisome factors that induce uterine tissue to form EMS lesions in vitro and in vivo. At the successful completion of this proposed research, the results are expected to have an important positive impact on the understanding of endometriosis. The data will contribute substantively to a mechanism based framework to elucidate endometriosis disease initiation that will, in turn, provide new opportunities for identifying targets for the development of novel therapeutics.