Endometriosis and Environmental Endocrine Disrupting Chemical Exposure

描述（由申请人提供）：子宫内膜异位症是一种由子宫内膜组织在子宫腔外异常生长引起的妇科疾病。这种疾病导致美国550万女性疼痛和/或不孕。每年的疾病成本负担超过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关键性质。患有子宫内膜异位症的妇女在子宫内膜和腹膜液的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，治疗方案有限。为了研究增强疾病的机制和毒物，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能力的宿主的腹膜腔中，用于子宫内膜异位症样疾病的发展。初步数据表明，子宫内膜中的ERα对病变附着和免疫细胞浸润至关重要，而腹腔环境中的ERα对子宫内膜异位症样病变对激素的反应至关重要。许多常见的内分泌干扰物质（EDCs）结合并激活ERα；在体外，它们对雌激素受体信号表现出剂量依赖性的激动剂/拮抗剂作用。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所必需的，(3)雌激素EDCs通过ERα信号增强子宫内膜异位症样病变的生长。下面的目的是为了用这个老鼠模型来检验这些假设。目的1将确定ERα在新血管生成和子宫内膜异位症样病变附着所必需的子宫内膜组织中的作用。目的2将确定ERα在腹膜中的作用(s)对完全子宫内膜异位症样病变反应性至关重要。目的3将探讨ERα在子宫内膜异位症样病变敏感性中的作用

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.