Dissecting the role of RPLP1 in female reproductive tract pathologies

项目摘要 子宫内膜是子宫的内层，由子宫内膜上皮和间质细胞组成。 还有其他的。子宫内膜上皮与间质的沟通是生殖成功的关键。 正常上皮和间质旁分泌和自分泌信号的干扰不仅损害了成功的 生殖，但也与子宫内膜病变，如子宫内膜异位症，子宫腺肌病和 子宫内膜癌。越来越多的证据表明子宫内膜的常见改变。 来自患有这些疾病的妇女的上皮细胞，例如上皮向间充质的转变。我们最近 通过确定RPLP1蛋白在子宫内膜中的过度表达，观察进一步有助于这一领域的研究 子宫内膜异位症、子宫腺肌症和子宫内膜癌患者的上皮细胞。本报告中的初步数据 应用进一步表明，RPLP1的过表达也可能影响孕酮的表达 受体和黄体酮信号。这是一个有趣的观察结果，因为子宫内膜异位症、子宫腺肌症和 子宫内膜癌的特点都是孕激素抵抗。为了扩展这些新奇的观察结果， 我们将检验子宫内膜上皮细胞RPLP1过度表达导致改变的特定假设 子宫内膜上皮细胞的分子图谱与增强的增殖、迁移和/或侵袭一致 上皮向间充质转化(EMT)以及孕激素信号转导。为了检验这一假设，有两个例子 这两种方法都利用了一种新的Rplp1在体内过表达的动物模型。 子宫内膜上皮细胞。特定目的我将识别上皮细胞Rplp1过度表达是否会导致受损 女性生育、子宫病变的发展和子宫内膜细胞类固醇信号的异常。特定目标 II将询问细胞成分和由上皮Rplp1过多引起的新的子宫分子通路- 表情。总的来说，在这项拨款申请中提出的实验将提供对这一角色的新见解 RPLP1在子宫内膜生理学和病理生理学中的作用可能导致更特异的发展 子宫内膜异位症、子宫腺肌病和/或子宫内膜疾病的治疗方式 癌症。

Project Summary The endometrium is the inner lining of the uterus and is composed of endometrial epithelial and stromal cells among others. Endometrial epithelial-stromal communication is essential for successful reproduction. Perturbations in normal epithelial and stromal paracrine and autocrine signaling not only impairs successful reproduction but are also associated with endometrial pathologies such as endometriosis, adenomyosis and endometrial cancer. There is a growing body of evidence that indicates common alterations in the endometrial epithelial cells from women with these diseases, such as epithelial to mesenchymal transitions. Our recent observations further contribute to this field by identifying over-expression of the RPLP1 protein in endometrial epithelial cells from women with endometriosis, adenomyosis and endometrial cancer. Preliminary data in this application further suggest that RPLP1 over-expression may also influence expression of the progesterone receptor and progesterone signaling. This is an intriguing observation in that endometriosis, adenomyosis and endometrial cancer are all characterized by progesterone resistance. To expand upon these novel observations, we will test the specific hypothesis that over-expression of endometrial epithelial cell RPLP1 leads to alterations in endometrial epithelial cell molecular profiles consistent with augmented proliferation, migration and/or invasion and epithelial to mesenchymal transition (EMT) as well as progesterone signaling. To test this hypothesis, two specific aims are proposed both of which utilize a novel in vivo animal model for Rplp1 over-expression in endometrial epithelial cells. Specific Aim I will discern if over-expression of epithelial Rplp1 leads to impaired female fertility, development of uterine pathologies, and aberrant endometrial cell steroid signaling. Specific Aim II will interrogate cellular constituents and novel uterine molecular pathways resulting from epithelial Rplp1 over- expression. Collectively, the experiments proposed in this grant application will provide new insight into the role of RPLP1 in endometrial physiology and pathophysiology which may lead to the development of more-specific treatment modalities for diseases of the endometrium such as endometriosis, adenomyosis and/or endometrial cancer.