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：
9097698
负责人：
Katherine Anne Burns
金额：
$ 24.63万
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 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9097698
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 Epidemiology Estrogen Receptor alpha Estrogen Receptors Estrogens Exhibits Exposure to Female Functional disorder Greater sac of peritoneum Growth Health Hormonal Hormones Human Immune Immune response Immune system Immunocompetent In Vitro Incidence Infertility Infiltration Inflammatory 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 estrogenic human disease immunoregulation insight mouse model novel novel therapeutics receptor expression research study 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.

描述（由申请人证明）：子宫内膜异位症是一种妇科驱散的子宫内膜组织生长，这种疾病会导致美国550万妇女的疼痛和/或不孕。十亿个疾病的常见疗法是抑制卵子的生产，并强调了子宫内膜异位症中trogen受体（ER）信号的关键。可以使用治疗选择。浸润环境至关重要，对激素的全体病和激素在体外激活。子宫内膜ERα是血管诊断信号传导所必需的（2）IC和炎症信号传导在子宫内膜异位状病变的发展中，以及（3）通过EERα的雌激素EDCS信号通过EERαtoteNotormodicos来的病变。 TES TET模型子宫内膜异位症样病变对子宫内膜异位症样疾病的雌激素疾病的作用将识别疾病的关键靶标，以阐明对子宫内膜异位症的暴露措施。