The Role of the Matrisome in Endometriosis Development

项目总结/摘要： 子宫内膜异位症是由于子宫内膜组织异常生长到子宫外而引起的妇科疾病。 子宫腔这种疾病导致慢性疼痛，月经极度疼痛，和/或不孕症，至少7.4 每年有100万美国女性。每年的成本负担超过700亿美元，没有治愈或有效的方法， 治疗是存在的。一种常见的治疗方法是抑制卵巢雌激素的产生，但一旦停止分泌， 治疗>70%的妇女报告有症状的疾病。子宫内膜异位症患者的免疫细胞增加 在他们的腹膜腔，往往有较高的发病率的自身免疫性疾病;然而，发病机制， 子宫内膜异位症的病因仍知之甚少。数据来自我们的子宫内膜异位症小鼠模型，其中供体 子宫组织自由分散到免疫活性宿主的腹膜腔中，揭示了 子宫内膜异位症的发生依赖于免疫系统。这些来自我们小鼠模型的数据 与女性的变化有关。我们的长期目标是为发展 机制为基础的战略，以预防，诊断和/或治疗子宫内膜异位症。这项建议的目的是 为了确定中性粒细胞和巨噬细胞介导的信号传导在子宫组织附着过程中的作用， 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MΦ分泌的基质体和基质体相关因子，促进和支持 EMS病变建立。以下目标旨在检验这一假设：目标1将确定 中性粒细胞群体，并表征其分泌的信号分子如何促进子宫内膜异位症 损伤附着。目标2将确定巨噬细胞的人口和特点如何分泌信号 分子有助于子宫内膜异位症病变存活。目标3将揭示诱导 子宫组织在体外和体内形成EMS损伤。在这项拟议的研究成功完成后， 该结果有望对子宫内膜异位症的认识产生重要的积极影响。数据 将实质上有助于一个机制为基础的框架，以阐明子宫内膜异位症疾病的启动， 反过来，将为确定新疗法的发展目标提供新的机会。

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.