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The Role of the Peritoneum in the Pathogenesis of Endometriosis

腹膜在子宫内膜异位症发病机制中的作用

基本信息

批准号：
9319317
负责人：
Quanxi Li
金额：
$ 19.83万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319317
关键词：
Address Affect Biological Models Cell Culture System Cells Chemicals Chronic Chronic Disease Development Diagnosis Disease Dose Endocrine Endocrine Disruptors Endometrial Epithelial Epithelial Cells Fibrosis Foundations Future Goals Growth Factor Human Immune In Vitro Infertility Inflammation Inflammatory Interstitial Cystitis Irritable Bowel Syndrome Lead Lesion Measures Mesenchymal Mesothelial Cell Mesothelium Methods Migraine Molecular Mus Nerve Fibers Pathogenesis Patients Pelvic Pain Peritoneal Peritoneal Fluid Peritoneal Mesothelial Cell Peritoneum Principal Investigator Process Productivity Proteomics Quality of life Research Research Proposals Resistance Retrograde Menstruation Role Site Small RNA Source System Testing Visceral Woman angiogenesis chemokine chronic pelvic pain cost cytokine endometriosis exosome implantation in vitro Model in vivo inflammatory marker inflammatory milieu microvesicles mono-(2-ethylhexyl)phthalate mouse model phthalates programs reproductive response transcriptome sequencing

项目摘要

Program Director/Principal Investigator (Last, First, Middle): Nowak, Romana A. Endometriosis is an inflammatory disease that affects 10% of women but is present in up to 70% of women with pelvic pain and 30% of women with infertility. The estimated cost of endometriosis is over $22 billion in the US alone (1), not counting associated chronic illnesses (migraine headache, irritable bowel syndrome and interstitial cystitis (2, 3). Thus it is safe to say that endometriosis is one of the costliest reproductive diseases in women not only in terms of treatment but also lost productivity and quality of life in affected patients. The most widely accepted hypothesis for development of endometriosis is retrograde menstruation that results in implantation of endometrial fragments on the visceral or peritoneal walls. Implantation of these fragments is thought to be regulated by factors secreted locally by immune cells and endometrial cells. However, the mechanisms by which endometrial cells are able to traverse the peritoneal mesothelium to establish lesions and how these lesions lead to increased inflammation and pelvic pain are not well understood. Our central hypothesis is that peritoneal mesothelial cells undergo epithelial-mesenchymal transition (EMT) in response to contact with endometrial cells and their secreted factors or with endocrine disrupting chemicals such as phthalates. This leads to a loss of peritoneal integrity allowing passage of endometrial cells into the peritoneum and induces expression of proinflammatory cytokines, chemokines and other factors that are secreted by mesothelial cells in exosomes/ microvesicles. The goal of this research proposal is to begin testing this hypothesis using an in vivo mouse model of endometriosis and an in vitro human mesothelial cell culture system to investigate the role of the peritoneal mesothelium in promoting the initiation of endometriotic lesions and how endocrine disrupters, phthalate, may affect peritoneal mesothelium and promote the development of a local inflammatory environment. We will test these hypotheses in the following two specific aims: 1) Characterize the secretome of human mesothelial cells undergoing EMT with loss of barrier integrity in an in vitro model system. We will perform small RNA sequencing and proteomic analysis of exosomes/microvesicles shed by primary human mesothelial cells undergoing EMT in an in vitro culture system. We will measure changes in trans-epithelial resistance to assess loss of barrier integrity during EMT. 2) Utilize an in vivo mouse model to investigate the process of EMT in mesothelium at sites of endometriotic lesions and the effects of phthalates on mesothelial cell EMT. We will assess changes in known EMT and inflammatory markers in early and established endometriotic lesions in mice treated with different doses of phthalates. Successful completion of these studies is expected to open up an entirely new direction in the field of endometriosis research and endocrine disrupters, providing a foundation for future studies focusing on basic mechanisms involved in inflammation and EMT and the mechanisms by which endocrine disrupters may contribute to chronic inflammation. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

项目总监/首席研究员（最后、第一、中间）：Nowak, Romana A. 子宫内膜异位症是一种炎症性疾病，影响 10% 的女性，但高达 70% 的女性存在子宫内膜异位症患有盆腔疼痛和30%的女性患有不孕症。子宫内膜异位症的估计费用超过 220 亿美元仅美国 (1)，不包括相关的慢性疾病（偏头痛、肠易激综合症和间质性膀胱炎 (2, 3)。因此可以肯定地说，子宫内膜异位症是世界上最昂贵的生殖疾病之一。妇女不仅在治疗方面受到影响，而且受影响患者的生产力和生活质量也受到影响。最子宫内膜异位症发展的广泛接受的假设是月经逆行，导致将子宫内膜碎片植入内脏或腹膜壁。这些片段的植入是据认为受到免疫细胞和子宫内膜细胞局部分泌的因子的调节。然而，子宫内膜细胞能够穿过腹膜间皮形成病变的机制这些病变如何导致炎症和盆腔疼痛加剧尚不清楚。我们的中央假设腹膜间皮细胞响应上皮-间质转化（EMT）与子宫内膜细胞及其分泌因子或内分泌干扰化学物质接触，例如邻苯二甲酸盐。这导致腹膜完整性丧失，使子宫内膜细胞无法进入子宫。腹膜并诱导促炎细胞因子、趋化因子和其他因子的表达由外泌体/微泡中的间皮细胞分泌。该研究计划的目标是开始测试该假设使用体内子宫内膜异位症小鼠模型和体外人间皮细胞培养物系统研究腹膜间皮在促进子宫内膜异位病变发生中的作用以及内分泌干扰物邻苯二甲酸盐如何影响腹膜间皮并促进腹膜间皮细胞的发育局部炎症环境。我们将在以下两个具体目标中测试这些假设： 1) 表征在屏障丧失的情况下经历 EMT 的人间皮细胞的分泌组体外模型系统的完整性。我们将进行小RNA测序和蛋白质组分析在体外培养中经历 EMT 的原代人间皮细胞脱落的外泌体/微泡系统。我们将测量跨上皮阻力的变化，以评估 EMT 期间屏障完整性的丧失。 2）利用体内小鼠模型研究间皮细胞EMT过程子宫内膜异位病变和邻苯二甲酸盐对间皮细胞 EMT 的影响。我们将评估以下方面的变化已知的 EMT 和炎症标志物在接受过治疗的小鼠的早期和已确定的子宫内膜异位病变中不同剂量的邻苯二甲酸盐。这些研究的成功完成预计将开辟一个全新的领域子宫内膜异位症研究和内分泌干扰物领域的方向，为未来奠定基础研究重点是炎症和 EMT 的基本机制以及炎症和 EMT 的机制内分泌干扰物可能会导致慢性炎症。 PHS 398/2590（修订版 06/09）页面延续格式页面