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：
10277800
负责人：
Vargheese Mani Chennathukuzhi
金额：
$ 64.27万
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/10277800
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 Knowledge Lead Mediating Mediator of activation protein Menstruation MicroRNAs Myometrial Neurons Non-Malignant Outcome Study Pain Pathogenesis Pathologic Pathway interactions Pelvic Pain Prognostic Marker RE1-silencing transcription factor Regulation Reporter Reporting Research 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 injury and repair innovation insight migration mouse model myometrium novel optimal treatments reproductive stem theories tissue injury 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.

项目概要子宫腺肌病是一种非恶性子宫疾病，以子宫内膜间质和腺体为特征在子宫肌层内。子宫腺肌症与月经量多、疼痛、盆腔疼痛有关。疼痛、性交疼痛和生殖功能障碍。然而，现在成像技术正在识别与选择子宫切除术的女性相比，子宫腺肌症发生在更年轻、更多样化的女性中，其中病理性诊断发生后，我们对临床疾病的许多假设正在发生变化。此外，唯一的子宫腺肌病、子宫切除术和激素抑制等被广泛接受和有效的治疗方法是对于这一更广泛的妇女群体来说，这是不可接受的。我们对诊断和治疗的许多不确定性子宫腺肌病源于我们对其发病机制的不确定性。子宫腺肌病最常见的理论开发重点是涉及组织损伤和修复机制，从而导致子宫腺肌症从子宫内膜基底层内陷到子宫肌层的发育（侵入/内陷）理论）。虽然新出现的数据支持这一理论的作用以及细胞迁移、增殖的参与子宫腺肌病发生发展过程中的介导和侵袭机制，详细了解其介导因素和机制显然缺乏。为了填补我们知识中的这一关键空白，我们将进行一系列实验，其中整合了明确的人类标本、新颖的小鼠模型和严格的体外方法来识别关键 REST-miRNA-组织重塑级联的组成部分，并证明了该途径的功能子宫腺肌症的发病机制。本申请中要测试的具体假设是减少子宫内膜和/或子宫肌层 REST 的表达诱导 miRNA 介导的组织发生改变重塑级联，增强子宫腺肌病的发展。为了检验这个假设，我们将描述子宫腺肌病中新型 REST-miRNA 介导的组织重塑途径的表达并定义 REST 使用新颖的实验小鼠模型发挥功能。使用体外模型进行细胞增殖、迁移和入侵，我们将破译子宫肌层-子宫内膜 REST-miRNA 组织之间的细胞间通讯与子宫腺肌病病理生理学相关的重塑通路信号传导。这些实验共同将提供关于 REST 在子宫腺肌病发展中的作用的新见解，进而可能导致识别该疾病的新治疗靶点。