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

项目摘要 子宫腺肌病是一种以子宫内膜间质和腺体为特征的非恶性子宫疾病。 在子宫肌层内。子宫腺肌病与月经过多和疼痛有关，盆腔 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 与选择病理子宫切除术的妇女相比，更年轻和更多样化的妇女患子宫腺肌病 随着诊断的发生，我们对临床疾病的许多假设正在改变。此外，唯一的 被广泛接受的治疗子宫腺肌病、子宫切除术和激素抑制的有效方法有 对于这一更广泛的女性群体来说是不可接受的。我们在诊断和治疗方面的大部分不确定性 子宫腺肌病源于我们对其发病机制的不确定。子宫腺肌病最常见的理论 发展集中在组织损伤和修复机制与由此导致的子宫腺肌病的参与上 从子宫内膜基底部凹陷到子宫肌层的发展(侵袭/凹陷 理论)。虽然新出现的数据支持这一理论的作用，并涉及细胞迁移、增殖 和侵袭性子宫腺肌病的发展，对介体和机制有详细的了解 显然是缺乏的。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，这些实验 定义明确的人体标本、新颖的小鼠模型和严格的体外方法来确定关键 Rest-miRNA-组织重塑的组件级联并展示了这一途径的功能 子宫腺肌病的发病机制。在此应用程序中要测试的特定假设是简化的 子宫内膜和/或肌层静息的表达诱导miRNA介导的组织改变 重塑级联，促进子宫腺肌病的发展。为了检验这一假设，我们将描绘 一种新的REST-miRNA介导的组织重塑通路在子宫腺肌病中的表达及其定义 使用新的实验小鼠模型实现功能。使用体外模型研究细胞的增殖、迁移和 侵袭，我们将破译子宫肌层-子宫内膜静止-miRNA组织之间的细胞间通讯 重塑通路信号与子宫腺肌病的病理生理相关。总而言之，这些实验将 为REST在子宫腺肌病发展中的作用提供了新的见解，并反过来可能导致识别 这种疾病的新治疗靶点。

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.