The Role of the Matrisome in Endometriosis Development

基质体在子宫内膜异位症发展中的作用

基本信息

批准号：
10630143
负责人：
Katherine Anne Burns
金额：
$ 43.15万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630143
关键词：
Adhesions Adolescent Affect American Autoimmune Diseases Cell Adhesion Cell Survival Cell physiology Cells Collagen Cytokine Signaling Data Development Diagnosis Disease Dysmenorrhea Endometrial Endometrium Estrogen Receptor alpha Estrogens Exhibits Extracellular Matrix Female Genital Diseases Goals Greater sac of peritoneum Growth Health Care Costs Human Immune Immune signaling Immune system Immunocompetent Immunocompromised Host Immunologic Surveillance Immunophenotyping In Vitro Incidence Infertility Inflammatory Innate Immune System Integrins Laparoscopic Surgical Procedures Lesion Macrophage Malignant neoplasm of ovary Mediating Menstrual fluid Menstruation Modeling Mus Ovarian Ablation Pain Pathogenesis Pathology Pathway interactions Peptide Initiation Factors Peritoneal Fluid Phase Phenotype Population Process Production Proteins Reporting Research Retrograde Menstruation Risk Risk Factors Role Signal Transduction Signaling Molecule Single Nucleotide Polymorphism Testing Tissues Uterine cavity Uterus Withholding Treatment Woman Work angiogenesis associated symptom cell type chronic pain chronic pelvic pain cost cytokine design diagnostic tool disability disabling symptom effective therapy endometriosis genome wide association study human disease immune cell infiltrate in vivo mouse model neutrophil new therapeutic target novel therapeutics prevent productivity loss recruit reproductive symptom treatment

项目摘要

PROJECT SUMMARY/ABSTRACT: Endometriosis is a gynecological disease resulting from abnormal growth of endometrial tissue outside the uterine cavity. This disease causes chronic pain, extreme pain with menstruation, and/or infertility in at least 7.4 million American women per year. The annual cost burden exceeds $70 billion and no cure or effective treatments exist. A common therapy is the suppression of ovarian estrogen production, but upon cessation of treatment >70% of women report symptomatic disease. Women with endometriosis have increased immune cells in their peritoneal cavity and often have higher incidences of autoimmune disorders; however, the pathogenesis of endometriosis remains poorly understood. Data from our mouse model of endometriosis, in which donor uterine tissue is freely dispersed into the peritoneal cavity of an immunocompetent host, has uncovered that initiation of endometriosis is dependent on the immune system. These data from our mouse model strongly correlate with alterations seen in women. Our long-term goal is to contribute toward the development of mechanism-based strategies to prevent, diagnose, and/or treat endometriosis. The objective in this proposal is to determine the role of neutrophil and macrophage mediated signaling on uterine tissue attachment during the immune-dependent phase of endometriosis. Therefore, we hypothesize the crosstalk among uterine cells, PMNs, and MΦs in women with EMS secrete matrisome and matrisome associated factors that promote and support EMS lesion establishment. The following aims are designed to test this hypothesis: Aim 1 will identify the neutrophil population and characterize how their secreted signaling molecules contribute to endometriosis lesion attachment. Aim 2 will identify the macrophage population and characterize how secreted signaling molecules contribute to endometriosis lesion survival. Aim 3 will uncover key matrisome factors that induce uterine tissue to form EMS lesions in vitro and in vivo. At the successful completion of this proposed research, the results are expected to have an important positive impact on the understanding of endometriosis. The data will contribute substantively to a mechanism based framework to elucidate endometriosis disease initiation that will, in turn, provide new opportunities for identifying targets for the development of novel therapeutics.

项目概要/摘要：子宫内膜异位症是指子宫内膜组织异常生长于子宫体以外而引起的妇科疾病。这种疾病至少会导致慢性疼痛、月经极度疼痛和/或不孕。每年有 100 万名美国妇女的费用负担超过 700 亿美元，而且没有治愈或有效的方法。现有的治疗方法是抑制卵巢雌激素的产生，但必须停止。治疗 >70% 的女性患有子宫内膜异位症，其免疫细胞增加。然而，其腹膜腔内自身免疫性疾病的发病率较高；我们对子宫内膜异位症小鼠模型的数据仍知之甚少，其中供体子宫组织自由分散到免疫活性宿主的腹膜腔中，发现子宫内膜异位症的发生强烈依赖于免疫系统。这些数据来自我们的小鼠模型。与女性身上发生的变化相关。我们的长期目标是为女性的发展做出贡献。该提案的目标是预防、诊断和/或治疗子宫内膜异位症的基于机制的策略。确定中性粒细胞和巨噬细胞介导的信号传导对子宫组织附着的作用因此，我们对抗子宫细胞、PMN 之间的串扰。患有 EMS 的女性中的 MΦ 和 MΦ 会分泌基质体和基质相关因子，以促进和支持 EMS 病变建立旨在检验这一假设：目标 1 将确定中性粒细胞群体并描述其分泌的信号分子如何导致子宫内膜异位症目标 2 将识别巨噬细胞群并表征分泌信号的方式。目标 3 将揭示诱导子宫内膜异位症病变存活的关键基质体因子。在成功完成这项拟议研究后，子宫组织在体外和体内形成 EMS 损伤。该结果预计将对子宫内膜异位症的理解产生重要的积极影响。将实质性地促进基于机制的框架，以阐明子宫内膜异位症疾病的发生反过来，将为确定开发新疗法的目标提供新的机会。