Dissecting the role of RPLP1 in female reproductive tract pathologies

项目摘要 子宫内膜是子宫的内层，由子宫内膜上皮细胞和间质细胞组成 还有其他的子宫内膜上皮-间质间的沟通是成功生殖的关键。 正常上皮和间质旁分泌和自分泌信号的扰动不仅损害了成功的 但是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异位症相关。 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女性的上皮细胞，例如上皮细胞向间质细胞的转化。我们最近 通过鉴定RPLP 1蛋白在子宫内膜中的过度表达， 子宫内膜异位症、子宫腺肌病和子宫内膜癌患者的上皮细胞。初步数据显示， 本申请进一步表明，RPLP 1过表达也可能影响孕酮的表达， 受体和孕酮信号传导。这是一个有趣的观察，子宫内膜异位症，子宫腺肌病和 子宫内膜癌的特征都是孕酮抵抗。为了扩展这些新的观察， 我们将检验子宫内膜上皮细胞RPLP 1的过度表达导致子宫内膜上皮细胞发生改变的特定假设， 在子宫内膜上皮细胞中，与增殖、迁移和/或侵袭增强一致的分子谱 和上皮间质转化（EMT）以及孕酮信号传导。为了验证这个假设，两个 提出了具体的目标，这两个目标都利用了一种新的Rplp 1过表达的体内动物模型， 子宫内膜上皮细胞具体目的我将辨别上皮Rplp 1的过度表达是否会导致受损的 女性生育力、子宫病变的发展和异常的子宫内膜细胞类固醇信号传导。具体目标 II将询问细胞成分和新的子宫分子途径，导致上皮Rplp 1超过- 表情总的来说，在这项拨款申请中提出的实验将提供新的见解的作用， RPLP 1在子宫内膜生理学和病理生理学中的作用，这可能导致更特异性的 子宫内膜疾病如子宫内膜异位症、子宫腺肌病和/或子宫内膜异位症的治疗方式 癌

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.