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

项目摘要 子宫腺肌病是一种非恶性子宫疾病，其特征是子宫内膜间质和腺体， 在子宫肌层内。子宫腺肌病与月经量大、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 子宫内膜异位症在年轻和更多样化的妇女比那些选择子宫切除术， 诊断发生时，我们对临床疾病的许多假设正在改变。此外，唯一 广泛接受的和有效的治疗子宫腺肌病，子宫切除术和激素抑制， 这对广大妇女群体来说是不可接受的。我们在诊断和治疗上的许多不确定性， 子宫腺肌病的发病机制尚不明确。子宫腺肌症最常见的理论 发展的中心是组织损伤和修复机制的参与，导致子宫腺肌病 从子宫内膜基底部内陷到子宫肌层的发展（侵袭/内陷 理论）。虽然新出现的数据支持这一理论的作用，并参与细胞迁移，增殖， 和侵袭在子宫腺肌病的发展，详细了解介质和机制， 明显缺乏。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， 定义明确的人类标本，新的小鼠模型和严格的体外方法，以确定关键的 REST-miRNA-组织重塑级联反应的组成部分，并证明了该途径的功能， 子宫腺肌病的发病机制。在本申请中待检验的具体假设是， 子宫内膜和/或子宫肌层REST的表达诱导miRNA介导的组织中的改变 重塑级联，增强子宫腺肌病的发展。为了验证这一假设，我们将描述 一种新的REST-miRNA介导的组织重塑途径在子宫腺肌病中的表达， 功能使用新的实验小鼠模型。使用细胞增殖、迁移和增殖的体外模型， 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构途径信号传导。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，反过来，可能导致识别 新的治疗靶点。

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.