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）：类似癌症的子宫内膜异位症也被证明是增生，侵袭和血管生成的特征。然而，这种雌激素依赖性，侵入性疾病的基本机制仍然未知。子宫内膜的两个主要细胞成分，即上皮（EEC）和基质（HESC）细胞，显示CXCR4和CXCL12蛋白的差异表达：子宫内膜上皮细胞表达的CXCR4水平高于基质细胞；相反，如先前从其他人和我们的实验室报道的那样，子宫内膜基质细胞表达了更高水平的CXCL12。同样，我们表明CXCR4表达在子宫内膜细胞系中受雌二醇（E2）和孕酮（P4）的差异调节。最后，我们还表明，在子宫内膜异位症和人类子宫内膜组织的大鼠模型的病变中，CXCR4显着表达。与分泌对照子宫内膜相比，子宫内膜损伤中CXCR4蛋白的表达显着高，该子宫内膜表达了该趋化因子受体的最高表达。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育和进展的关键步骤。具体而言，该建议旨在研究其配体CXCL12引起的CXCR4信号在促进子宫内膜异位症中细胞增殖，侵袭和血管生成中的作用。推动该建议的主要假设是，在子宫内膜液中的CXCR4蛋白过度表达了月经流体中腹膜腔的过表达，并且其通过CXCL12的未经特点激活，刺激了增殖，侵袭和血管生成，导致病变。为了检验这些假设，首先将在子宫内膜和子宫内膜细胞的背景下评估CXCR4-CXCL12轴在诱导增殖以及侵袭/迁移机制中的功能（特定目标＃1）。接下来，将确定由CXCL12在这些细胞环境中与CXCR4结合的分子机制（特定目标＃2）。在特定的目标＃3中，CXCR4抑制剂CTCE-9908在防止子宫内膜异位症的发展中的功效将在体内使用良好的子宫内膜异位症模型在体内评估。我们推测，子宫内膜组织中的基质细胞以旁分泌方式产生CXCL12，从而产生了一种微环境，以诱导表达CXCR4表达上皮细胞的生存。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，入侵和生存以及炎症反应如何提供适当的细胞环境以诱导异位位置的子宫内膜细胞存活。此外，这些研究将为针对CXCR4-CXCL12轴的这种无法治愈的状况提供未来治疗方式的见解。公共卫生相关性：子宫内膜异位症在其生殖生活中影响数百万妇女，从而导致疼痛和不育。无法治愈，治疗受到限制。该疾病的特征是骨盆区域炎症。这项研究将研究炎症分子CXCR4在子宫内膜异位症发展以及阻断其作用是否可以代表该疾病的新治疗方法中的作用。