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Endometriosis and Environmental Endocrine Disrupting Chemical Exposure

子宫内膜异位症和环境内分泌干扰化学物质暴露

基本信息

批准号：
9308966
负责人：
Katherine Anne Burns
金额：
$ 24.24万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9308966
关键词：
Adult Affect Agonist Angiogenic Factor Autoimmune Diseases Biological Markers Cells Chemical Exposure Chemicals Chemosensitization Chemotactic Factors Clinical Data Data Detection Development Diagnosis Disease Disease Progression Dose Dysmenorrhea Endocrine Disruptors Endometrial Endometrium Environment Environmental Exposure Environmental Risk Factor Estrogen Receptor alpha Estrogen Receptors Estrogens Etiology Exhibits Exposure to Female Female Genital Diseases Functional disorder Greater sac of peritoneum Growth Hormonal Hormones Human Immune Immune response Immune system Immunocompetent In Vitro Incidence Infertility Infiltration Inflammatory Injectable Injection of therapeutic agent Knock-out Knowledge Lead Lesion Location Mediating Morbidity - disease rate Mus Nature Nuclear Receptors Operative Surgical Procedures Ovarian Ablation Pain Pathogenesis Pelvic cavity structure Peritoneal Peritoneal Fluid Peritoneal Macrophages Peritoneum Play Preventive measure Production Quality of life Receptor Signaling Recruitment Activity Reproductive Health Research Retrograde Menstruation Risk Role Signal Transduction Symptoms Testing Tissues Toxic Environmental Substances Uterine cavity Wild Type Mouse Woman angiogenesis bisphenol A blood vessel development burden of illness cell type chemical binding chronic pain cost design endometriosis enhancing factor epidemiologic data estrogenic experimental study human disease immunoregulation insight mouse model negative affect novel novel therapeutics public health relevance receptor expression response therapy development toxicant treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Endometriosis is a gynecological disease resulting from abnormal growth of endometrial tissue outside the uterine cavity. This disease causes pain and/or infertility in 5.5 million women in the US. The annual cost burden of disease is greater than $22 billion and no cure exists. A common therapy for disease is the suppression of ovarian estrogen production and emphasizes the critical nature of altered estrogen receptor (ER) signaling in endometriosis. Women with endometriosis have aberrant ER expression in the endometrium and in immune cells of the peritoneal fluid. Often, women with endometriosis have higher incidences of autoimmune disorders. However, the pathogenesis of endometriosis remains poorly understood and limited treatment options are available. To investigate mechanisms and toxicants that potentiate disease, a unique endometriosis mouse model was developed to mimic human disease. Minced donor uterine tissue is freely dispersed into the peritoneal cavity of an immunocompetent host for the development of endometriosis-like disease. Initial data demonstrates that ERα in the endometrium is critical for lesion attachment and immune cell infiltration, and ERα in the peritoneal cavity environment is critical for full endometriosis-like lesion responsiveness to hormone. A number of prevalent endocrine disrupting chemicals (EDCs) bind to and activate ERα; in vitro, they exhibit dose-dependent agonist/antagonist effects on estrogen receptor signaling. To determine the mechanism(s) of action of these findings the hypotheses are (1) Endometrial ERα is required for angiogenic signaling, (2) Peritoneal ERα is required for chemotactic and inflammatory signaling in the development of endometriosis-like lesions, and (3) Estrogenic EDCs signal through ERα to potentiate endometriosis- like lesion growth. The following aims are designed to test these hypotheses using this mouse model. Aim 1 will determine the role(s) of ERα in endometrial tissue essential for neo-angiogenesis and endometriosis- like lesion attachment. Aim 2 will determine the role(s) of ERα in the peritoneum critical for full endometriosis- like lesion responsiveness. Aim 3 will investigate the role of ERα in endometriosis-like lesions sensitivity to estrogenic EDC exposure. Understanding the actions of ERα in endometriosis-like disease will identify key targets of angiogenesis and immune modulations involved in disease as well as clarify the effects of EDC exposure on endometriosis. These findings will inform of useful biomarkers for disease detection and preventative measures to limit exposure to environmental toxicants to reduce the risk of endometriosis.

子宫内膜异位症是一种妇科疾病，是由于子宫内膜组织在子宫腔外异常生长而引起的。这种疾病导致美国550万妇女的疼痛和/或不孕症。每年的疾病费用负担超过220亿美元，而且没有治愈方法。一种常见的治疗方法是抑制卵巢雌激素的产生，并强调改变雌激素受体（ER）信号在子宫内膜异位症中的重要性。子宫内膜异位症患者的子宫内膜和腹腔液免疫细胞中有异常的ER表达。通常，患有子宫内膜异位症的女性有更高的自身免疫性疾病的发病率。然而，子宫内膜异位症的发病机制仍然知之甚少，治疗选择有限。为了研究加剧疾病的机制和毒物，开发了一种独特的子宫内膜异位症小鼠模型来模拟人类疾病。切碎的供体子宫组织自由分散到免疫活性宿主的腹膜腔中，用于发生子宫内膜异位症样疾病。初步数据表明，子宫内膜中的ERα对于病变附着和免疫细胞浸润至关重要，而腹腔环境中的ERα对于激素对子宫内膜样病变的完全反应至关重要。许多普遍存在的内分泌干扰物（EDCs）结合并激活ERα;在体外，它们对雌激素受体信号传导表现出剂量依赖性激动剂/拮抗剂效应。为了确定这些发现的作用机制，假设是（1）子宫内膜ERα是血管生成信号传导所必需的，（2）腹膜ERα是子宫内膜异位症样病变发展中趋化和炎症信号传导所必需的，（3）雌激素性EDC通过ERα信号传导促进子宫内膜异位症样病变生长。以下目的旨在使用该小鼠模型测试这些假设。目的1探讨ERα在子宫内膜新生血管形成和子宫内膜异位样病变附着中的作用。目的2将确定ERα在腹膜中的作用，这对子宫内膜异位症样病变的完全反应至关重要.目的3：探讨ERα在类银屑病样病变中的作用，雌激素EDC暴露。了解ERα在子宫内膜异位症样疾病中的作用将确定疾病中涉及的血管生成和免疫调节的关键靶点，并阐明EDC暴露对子宫内膜异位症的影响。这些发现将为疾病检测和预防措施提供有用的生物标志物，以限制暴露于环境毒物，降低子宫内膜异位症的风险。