Role of the CXCR4/CXCL12 axis in endometriosis

CXCR4/CXCL12轴在子宫内膜异位症中的作用

基本信息

批准号：
8400555
负责人：
Abigail Ruiz-Rivera
金额：
$ 3.1万
依托单位：
PONCE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2014-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8400555
关键词：
Affect Amino Acids Area Automobile Driving Binding Biological Assay Bromodeoxyuridine CXCL12 gene CXCR4 gene Cell Line Cell Proliferation Cell Survival Cells Coculture Techniques Development Disease Endometrial Endometrial Stromal Cell Endometrium Endothelial Cells Environment Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Estradiol Estrogens Future Gene Expression Greater sac of peritoneum Human Immigration Immunohistochemistry Incubated Infertility Infiltration Inflammation Inflammatory Invaded KDR gene Knowledge Laboratories Lead Lesion Life Ligands Liquid substance Location Malignant Neoplasms Measures Menstrual fluid Modality Modeling Molecular Neoplasm Metastasis Operative Surgical Procedures Pain Pelvis Peptides Peritoneal Phosphorylation Progesterone Proliferating Proteins Proto-Oncogene Proteins c-akt Rattus Reaction Recombinants Reporting Role Signal Transduction Site Small Interfering RNA Specificity Stromal Cell-Derived Factor 1 Stromal Cells System Testing Therapeutic Tissues Vascular Endothelial Growth Factors Western Blotting Woman angiogenesis base cell growth chemokine receptor endometriosis in vivo indexing inhibitor/antagonist insight matrigel migration neutralizing antibody novel overexpression paracrine prevent protein expression receptor reproductive response tumor progression

项目摘要

DESCRIPTION (provided by applicant): Endometriosis, like cancer, has also been shown to be characterized by increased proliferation, invasion and angiogenesis; however, the specific mechanisms underlying this estrogen-dependent, invasive disease are still unknown. The two main cellular components of the endometrium, namely epithelial (EEC) and stromal (HESC) cells, show a differential expression of CXCR4 and CXCL12 proteins: endometrial epithelial cells express higher CXCR4 levels than stromal cells; conversely, endometrial stromal cells expressed higher levels of CXCL12 as previously reported from others and our laboratory. Also, we showed that CXCR4 expression is differentially regulated by estradiol (E2) and progesterone (P4) in endometrial cell lines. Finally, we have also shown that CXCR4 is significantly overexpressed in the lesions of the rat model of endometriosis as well as in human endometriotic tissues. The expression of CXCR4 protein in the endometriotic lesions was significantly higher compared to secretory control endometrium, which expresses the highest expression of this chemokine receptor. Based on these preliminary observations, we hypothesize that activation of the CXCR4-CXCL12 axis is a key step in the development and progression of endometriosis. Specifically, this proposal aims to investigate the role of CXCR4 signaling induced by its ligand, CXCL12, in promoting cell proliferation, invasion, and angiogenesis in endometriosis. The main hypothesis driving this proposal is that overexpression of CXCR4 protein in endometriotic epithelial cells reaching the peritoneal cavity in the menstrual fluid, and its unchartered activation by CXCL12, stimulates proliferation, invasion, and angiogenesis leading to lesion establishment. To test these hypotheses, first the functionality of the CXCR4-CXCL12 axis in inducing proliferation as well as invasion/migration mechanisms will be assessed in the context of endometrial and endometriotic cells (Specific Aim #1). Next, the molecular mechanisms activated by CXCL12 binding to CXCR4 in these cellular contexts will be determined (Specific Aim #2). In Specific Aim #3, the efficacy of the CXCR4 inhibitor CTCE-9908 in preventing the development of endometriosis will be assessed in vivo using a well-validated rat model of endometriosis. We speculate that stromal cells in the endometriotic tissue produce CXCL12 in a paracrine manner, thus creating a microenvironment inducive to survival of CXCR4-expressing epithelial cells. The knowledge that will be gained from this project is important to understand how endometrial cells are able to proliferate, invade and survive in ectopic sites and how the inflammatory reaction can provide the appropriate cell environment to induce endometrial cell survival at ectopic locations. Also, these studies will provide insights fo the development of future therapeutic modalities for this incurable condition targeting the CXCR4-CXCL12 axis. PUBLIC HEALTH RELEVANCE: Endometriosis affects millions of women during their reproductive life causing pain and infertility. No cure is available, and treatments are limited. This disease is characterized by inflammation in the pelvic area. This study will investigate the role of an inflammatory molecule, CXCR4, in the development of endometriosis and whether blocking its action could represent a novel treatment for this disease.

描述（由申请人提供）：子宫内膜异位症与癌症一样，也被证明具有增殖、侵袭和血管生成增加的特征；然而，这种雌激素依赖性侵袭性疾病的具体机制仍不清楚。子宫内膜的两种主要细胞成分，即上皮细胞 (EEC) 和基质细胞 (HESC)，显示出 CXCR4 和 CXCL12 蛋白的差异表达：子宫内膜上皮细胞比基质细胞表达更高的 CXCR4 水平；相反，正如其他人和我们实验室之前报道的那样，子宫内膜基质细胞表达更高水平的 CXCL12。此外，我们还发现子宫内膜细胞系中 CXCR4 的表达受到雌二醇 (E2) 和孕酮 (P4) 的差异调节。最后，我们还发现CXCR4在子宫内膜异位症大鼠模型的病变以及人类子宫内膜异位组织中显着过表达。子宫内膜异位病灶中CXCR4蛋白的表达显着高于分泌对照子宫内膜，该趋化因子受体的表达量最高。基于这些初步观察，我们假设 CXCR4-CXCL12 轴的激活是子宫内膜异位症发生和进展的关键步骤。具体来说，该提案旨在研究其配体CXCL12诱导的CXCR4信号传导在促进子宫内膜异位症细胞增殖、侵袭和血管生成中的作用。推动这一提议的主要假设是，子宫内膜异位上皮细胞中 CXCR4 蛋白在经液中到达腹腔，CXCR4 蛋白被 CXCL12 未知地激活，刺激增殖、侵袭和血管生成，导致病变建立。为了检验这些假设，首先将在子宫内膜和子宫内膜异位细胞的背景下评估 CXCR4-CXCL12 轴在诱导增殖以及侵袭/迁移机制中的功能（具体目标#1）。接下来，将确定这些细胞环境中 CXCL12 与 CXCR4 结合激活的分子机制（具体目标 #2）。在具体目标#3中，将使用经过充分验证的子宫内膜异位症大鼠模型在体内评估 CXCR4 抑制剂 CTCE-9908 在预防子宫内膜异位症发展方面的功效。我们推测子宫内膜异位组织中的基质细胞以旁分泌方式产生CXCL12，从而创造诱导表达CXCR4的上皮细胞存活的微环境。从该项目中获得的知识对于了解子宫内膜细胞如何能够在异位部位增殖、侵入和存活以及炎症反应如何提供适当的细胞环境以诱导子宫内膜细胞在异位部位存活非常重要。此外，这些研究将为这种针对 CXCR4-CXCL12 轴的不治之症的未来治疗方式的开发提供见解。公共卫生相关性：子宫内膜异位症影响着数百万女性的生育期，导致疼痛和不孕。目前尚无治愈方法，治疗方法也有限。这种疾病的特征是骨盆区域的炎症。这项研究将调查炎症分子 CXCR4 在子宫内膜异位症发展中的作用，以及阻断其作用是否可以成为治疗这种疾病的新方法。