Endometriosis and Environmental Endocrine Disrupting Chemical Exposure

说明(申请人提供)：子宫内膜异位症是子宫腔外子宫内膜组织异常生长引起的一种妇科疾病。在美国，这种疾病导致550万女性疼痛和/或不孕。每年疾病的成本负担超过220亿美元，而且目前还没有治愈方法。一种常见的疾病治疗方法是抑制卵巢雌激素的产生，并强调雌激素受体(ER)信号改变在子宫内膜异位症中的关键性质。子宫内膜异位症患者在子宫内膜和腹腔液免疫细胞中都有ER的异常表达。通常情况下，患有子宫内膜异位症的女性自身免疫性疾病的发生率更高。然而，子宫内膜异位症的发病机制仍然知之甚少，治疗方案也有限。为了研究加重疾病的机制和毒物，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被自由地分散到具有免疫活性的宿主的腹膜腔内，以发展为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的渗透至关重要，而腹膜环境中的ERα对于子宫内膜异位症样病变对激素的充分反应是至关重要的。许多流行的内分泌干扰物(EDCs)结合并激活ERα；在体外，它们在雌激素受体信号转导中表现出剂量依赖的激动剂/拮抗剂效应。为了确定这些发现的作用机制(S)，假设(1)子宫内膜ERα需要血管生成信号，(2)腹膜ERα需要趋化和炎症信号在子宫内膜异位症样病变的发展中，以及(3)雌激素样EDCs信号通过ERα促进子宫内膜异位症样病变的生长。以下目的是为了使用这个小鼠模型来检验这些假设。目的1确定ERα在子宫内膜组织中对新生血管生成和子宫内膜异位症样病变附着所必需的作用(S)。目的2将确定ERα在腹膜中对子宫内膜异位症样病变的充分反应至关重要的作用(S)。目的3将研究ERα在子宫内膜异位症样病变对 雌激素类EDC暴露。了解ERα在子宫内膜异位症样疾病中的作用，将有助于确定与疾病相关的血管生成和免疫调节的关键靶点，并阐明EDC暴露在子宫内膜异位症中的作用。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，以限制环境毒物的暴露，以降低子宫内膜异位症的风险。

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.