Molecular mechanisms of gap junction promotion of lesion formation in Endometriosis

间隙连接促进子宫内膜异位症病变形成的分子机制

• 批准号: 10490427
• 负责人: BRUCE J NICHOLSON
• 金额: $ 43.58万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490427
• 关键词: Adenoviruses; Adhesions; Adhesives; Affect; Animals; Antibodies; Behavior; CD44 gene; Cell Compartmentation; Cells; Characteristics; Connexin 43; Coupling; Development; Diagnostic; Disease; Disease Progression; Disseminated Malignant Neoplasm; Down-Regulation; Endometrial; Endometrium; Environment; Epithelial; Epithelial Cells; Event; Extravasation; Fertility; Fingerprint; Functional disorder; Gap Junctions; Gene Expression; Genes; Genomics; Goals; HMMR gene; Harvest; Hyaluronic Acid; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Infection; Invaded; Lead; Lesion; Mediating; Mesothelium; Modification; Molecular; Mus; Neoplasm Metastasis; Pain; Pathogenesis; Pathogenicity; Pathology; Patients; Peritoneal; Peritoneal Mesothelial Cell; Peritoneum; Phenotype; Play; Process; Property; Proteomics; Retrograde Menstruation; Role; Scaffolding Protein; Seeds; Series; Signal Pathway; Signal Transduction; Soil; Stromal Cells; System; Testing; Tissues; Up-Regulation; Woman; base; cell behavior; collaborative environment; endometriosis; epithelial to mesenchymal transition; in vitro Model; in vivo; intercellular communication; mutant; natural Blastocyst Implantation; novel; receptor; response; single-cell RNA sequencing; small hairpin RNA; therapeutic target; transplant model

Invasive cell behavior is a component of normal (blastocyst implantation, extravasation) and pathogenic processes (metastasis, endometriosis), and is initiated by heterotypic contacts between cells. There is strong evidence, particularly in metastatic cancer, that gap junction (GJ) mediated intercellular coupling (GJIC) between the invading cells and target tissue plays a critical role. Yet gap junctions have not been studied in the most common invasive pathogenesis endometriosis. Endometriosis is thought to arise through retrograde menstruation of endometrial tissue to the peritoneum (occurring in most women), but there is active debate as to whether the disease is due to changes in the endometrium (the seed) or a permissive peritoneal environment (the soil). Project 1 demonstrated a striking downregulation of GJ genes in stromal cells (ESCs), and an inverse upregulation in epithelial cells (EECs) that follows the progression of the disease, and could serve as a diagnostic. Here we show that ESCs from endometriosis patients are unique in showing a large induction of GJIC upon interaction with peritoneal mesothelial cells (PMCs). This heterotypic GJIC was critical for the ESC invasiveness by inducing a disruption of the barrier function of the mesothelium. Conversely, PMCs also selectively affect ESCs from endometriosis patients by triggering Cx43 assembly into GJs, and by inducing a Mesenchymal to Epithelial Transition (MET). These results lend strong support the seed hypothesis. The current proposal builds on these results within the collaborative environment of a P01 that will allow a comprehensive analysis of how intercellular interactions in endometriosis lead to lesion formation. This will include understanding: (a) How GJ, and related adhesive genes, are regulated in endometriosis (Project 1); (b) how ESCs and PMCs initially recognize and stably adhere to one another (Project 3), leading to GJ formation, and; (c) how these GJs induce both modification of the PMC barrier function and promote ESC invasive behavior (Project 2). The goals of Project 2 will be achieved through three aims: Aim 1: Establish what functions of Cx43 are important for initiating invasiveness (i.e. GJIC, hemichannels, protein scaffolds) (1.1) and identify the molecular changes induced in PMCs that disrupt barrier function (1.2).

侵袭性细胞行为是正常（胚泡着床、外渗）和致病性的组成部分