REST/NRSF, miRNAs, and tissue remodeling in adenomyosis pathophysiology

子宫腺肌症病理生理学中的 REST/NRSF、miRNA 和组织重塑

基本信息

批准号：
10617304
负责人：
Vargheese Mani Chennathukuzhi
金额：
$ 63.62万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-09 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617304
关键词：
3&apos Untranslated Regions Adenomyosis Biological Biological Assay Cell Communication Cell Proliferation Cells Clinical Data Development Diagnosis Disease Disease Progression Endometrial Endometrium Epithelial Cells Event Experimental Models Functional disorder Gene Expression Gland Hormonal Human Hysterectomy Image In Vitro Invaded Knockout Mice Knowledge Mediating Mediator Menstruation MicroRNAs Myometrial Neurons Non-Malignant Outcome Study Pain Pathogenesis Pathologic Pathway interactions Pelvic Pain Prognostic Marker Proliferating RE1-silencing transcription factor Regulation Reporter Reporting Repression Research Rest Role Series Signal Pathway Smooth Muscle Specimen Testing Tissues Transcription Repressor Uncertainty Uterine Diseases Uterus Woman Women&apos s Group cell motility conditional knockout diagnostic biomarker effective therapy endometrial stroma experimental study in vitro Model innovation insight migration mouse model myometrium novel optimal treatments reproductive stem theories tissue injury tissue repair transcription factor transcription factor REST transcriptome sequencing young woman

项目摘要

Project Summary Adenomyosis is a nonmalignant uterine disease characterized by endometrial stroma and glands found within the myometrium. Adenomyosis has been associated with heavy and painful menstrual periods, pelvic pain, pain with intercourse, and reproductive dysfunction. However, now that imaging is identifying adenomyosis in younger and more varied women than those electing hysterectomy where pathological diagnosis occurred, many of our assumptions about the clinical disease are changing. Additionally, the only widely accepted and effective treatments for adenomyosis, hysterectomy and hormonal suppression, are unacceptable for this wider group of women. Much of our uncertainty on diagnosis and treatment for adenomyosis stem from our uncertainty on its' pathogenesis. The most common theory of adenomyosis development centers on the involvement of tissue injury and repair mechanisms with resulting adenomyosis development from invagination of the endometrial basalis into the myometrium (the invasion/invagination theory). While emerging data support a role for this theory and the involvement of cell migration, proliferation and invasion in adenomyosis development, a detailed understanding on the mediators and mechanisms is clearly lacking. To fill this critical gap in our knowledge we will perform a series of experiments which integrate well-defined human specimens, novel mouse models and rigorous in vitro approaches to identify key components of a REST-miRNA-tissue remodeling cascade and demonstrate the functionality of this pathway in the pathogenesis of adenomyosis. The specific hypothesis to be tested in this application is that reduced expression of endometrial and/or myometrial REST induces alterations in a miRNA-mediated tissue remodeling cascade which augments adenomyosis development. To test this hypothesis, we will delineate expression of a novel REST-miRNA mediated tissue remodeling pathway in adenomyosis and define REST's function using novel experimental mouse models. Using in vitro models for cell proliferation, migration and invasion, we will decipher cell to cell communication between myometrial-endometrial REST-miRNA tissue remodeling pathway signaling relevant to adenomyosis pathophysiology. Together, these experiments will provide novel insight into the role of REST in adenomyosis development and in turn, may lead to identification of novel treatment targets for this disease.

项目摘要腺肌病是一种非恶性子宫疾病，其特征是子宫内膜基质和发现的腺体在子宫内。腺肌病与重度月经时期有关，骨盆疼痛，性交疼痛和生殖功能障碍。但是，现在成像正在识别年轻女性和多样化女性的子宫肌病比选举病理性的子宫切除术诊断发生了，我们对临床疾病的许多假设正在发生变化。另外，唯一的广泛接受且有效治疗子宫肌症，子宫切除术和激素抑制是对于这个更广泛的妇女来说，无法接受。我们对诊断和治疗的不确定性腺肌病源于我们对其发病机理的不确定性。腺肌病最常见的理论开发集中于组织损伤和修复机制与产生的子宫腺癌从子宫内膜底层侵入中的发育理论）。在新兴数据支持该理论的作用和细胞迁移的参与时，增殖和腺肌发育中的入侵，对介体和机制的详细理解是显然缺乏。为了填补我们的知识，我们将执行一系列集成的实验定义明确的人类标本，新型鼠标模型和严格的体外方法，以识别钥匙休息 - rirna组织的组件重塑级联反应，并演示该途径的功能子宫肌病的发病机理。在本应用程序中要检验的特定假设是减少子宫内膜和/或肌层休息的表达诱导miRNA介导的组织改变重塑级联反应增强了腺肌病的发展。为了检验这一假设，我们将描述新型静息miRNA介导的组织重塑途径的表达，并定义REST的途径使用新型实验鼠标模型的功能。使用体外模型进行细胞增殖，迁移和入侵，我们将使细胞对肌层内静脉静脉内组织之间的细胞通信解密重塑途径信号与腺癌病理生理学有关。这些实验将在一起提供有关休息在腺肌发育中的作用的新颖洞察力，然后可能导致识别这种疾病的新型治疗目标。