Role of REST in endometriosis-associated progesterone resistance

项目摘要 子宫内膜异位症是一种重要的女性疾病，其特征是不孕和盆腔疼痛， 子宫内膜间质和腺体组织在异位位置生长。一些因素，如贫困 卵母细胞质量、着床障碍和孕激素抵抗被认为是影响因素 与糖尿病相关的不孕症，但确切的机制知之甚少。孕酮 抵抗被认为影响异位（异位病变）和在位子宫内膜。改变 异位病变组织的反应性被认为有助于异位组织的存活， 虽然认为在位子宫内膜不能充分响应孕酮是导致 与疾病有关的不孕症。许多研究表明， 子宫内膜异位症，子宫内膜孕酮靶基因的错误表达。关于分子的几种理论 已经提出了子宫内膜异位症中孕酮抵抗的基础，包括 孕酮受体（PGR）-A和PGR-B，以及炎症、遗传学和表观遗传学。但 这种耐药性的确切机制尚未完全阐明。因此，在我们的国家中仍然存在着一个关键的差距。 关于子宫内膜异位症女性的子宫内膜（在位和异位）为何表现出改变的知识 孕酮反应性 支持这一应用的初步研究结果表明，神经元限制性蛋白质的表达， 沉默因子/RE 1沉默转录因子，REST在原位和异位中均缺失/严重减少 子宫内膜异位症妇女的增生性病变组织。REST是一种转录抑制因子， 抑制非神经元组织中的神经元基因表达，但也可以作为基因表达的增强子。 在子宫内膜组织中，孕酮的作用可能与此类似。当前 这项研究将扩展我们的初步研究结果，并检验这一假设，即在原位细胞中REST表达的丧失， 和异位子宫内膜导致不能充分响应孕酮，这分别导致 导致不能生育后代（不育），并使病变存活持续。这 这一假设将在两个具体目标下进行检验，这两个目标将：1）描述在哺乳动物中的REST-孕酮途径， 异位和在位子宫内膜，并验证REST在调节孕酮靶基因中的作用， 2)证明REST在子宫内膜异位症中调节孕酮反应性的功能必要性- 相关的不孕症和疼痛以及基质到上皮细胞到细胞的信号传导。本研究的结果 将提供新的洞察作用休息作为一个调解人的孕酮行动，并将导致识别 新的REST/孕酮靶点可能作为子宫内膜异位症的未来治疗靶点 治疗

Project Summary Endometriosis is a significant female disease characterized by infertility and pelvic pain in which endometrial stromal and glandular tissue grow in ectopic locations. Several contributing factors such as poor oocyte quality, impaired implantation and progesterone resistance have been implicated as contributing factors to endometriosis-associated infertility, yet the precise mechanisms are poorly understood. Progesterone resistance is thought to influence both the ectopic (endometriotic lesion) and eutopic endometrium. Altered responsiveness of endometriotic lesion tissue is proposed to contribute to the survival of the ectopic tissue, while inability of eutopic endometrium to adequately respond to progesterone is believed to contribute to the infertility associated with the disease. Numerous studies have demonstrated that in women with endometriosis, endometrial progesterone target genes are misexpressed. Several theories on the molecular basis of progesterone resistance in endometriosis have been put forth including altered expression of progesterone receptors (PGR)-A and PGR-B, as well as inflammation, genetics, and epigenetics. However, the exact mechanism of this resistance has yet to be fully elucidated. Thus, there remains a critical gap in our knowledge as to why endometrium (both eutopic and ectopic) from women with endometriosis exhibits altered progesterone responsiveness. Preliminary findings in support of this application suggest that protein expression of the neuron-restrictive silencer factor/RE1-silencing transcription factor, REST is absent/severely reduced in both eutopic and ectopic endometriotic lesion tissue in women with endometriosis. REST is a transcriptional repressor that primarily represses neuronal gene expression in non-neuronal tissues, but can also act as an enhancer of gene transcription and may function in a similar capacity for progesterone action in endometrial tissue. The current study will expand upon our preliminary findings and test the hypothesis that loss of REST expression in eutopic and ectopic endometrium leads to an inability to adequately respond to progesterone, which respectively leads to an inability to produce offspring (infertility) and allows persistence of endometriotic lesion survival. This hypothesis will be tested under two specific aims which will: 1) delineate the REST-progesterone pathway in ectopic and eutopic endometrium and verify the role of REST in regulation of progesterone target genes, and 2) demonstrate functional necessity of REST in regulation of progesterone responsiveness in endometriosis- associated infertility and pain as well as stromal to epithelial cell to cell signaling. Outcomes from this study will provide new insight into the role of REST as a mediator of progesterone action and will lead to identification of novel REST/progesterone targets which may be serve as future therapeutic targets for endometriosis treatment.