Dissecting the role of RPLP1 in female reproductive tract pathologies

剖析 RPLP1 在女性生殖道病理中的作用

基本信息

批准号：
10705087
负责人：
Warren B Nothnick
金额：
$ 23.25万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705087
关键词：
Adenomyosis Animal Model Applications Grants Autocrine Communication Cell Proliferation Cell physiology Cells Communication Coupled Data Development Disease Endometrial Endometrial Carcinoma Endometrial Hyperplasia Endometrium Environment Epithelial Cells Epithelial-Stromal Communication Epithelium Estrogens Exhibits Female Fertility Functional disorder Impairment In Vitro Infertility Invaded Laboratories Lactoferrin Lead Literature Mediator Modality Modeling Molecular Molecular Profiling Mus Organ Paracrine Communication Partner in relationship Pathology Pathway interactions Physiology Play Process Progesterone Progesterone Receptors Proliferating Proteins Reproduction Reproductive Process Resistance Role Signal Pathway Signal Transduction Steroid Receptors Steroids Stromal Cells Testing Transcript Uterine Diseases Uterus Woman cell stroma endometriosis epithelial to mesenchymal transition eutopic endometrium experimental study female fertility gain of function in vivo insight migration mouse model novel overexpression protein expression receptor expression reproductive tract response single-cell RNA sequencing

项目摘要

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.

项目概要子宫内膜是子宫内膜，由子宫内膜上皮细胞和间质细胞组成除其他外。子宫内膜上皮间质通讯对于成功繁殖至关重要。正常上皮和基质旁分泌和自分泌信号的扰动不仅会损害成功生殖，但也与子宫内膜病变有关，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存在常见的改变来自患有这些疾病的女性的上皮细胞，例如上皮细胞到间质细胞的转变。我们最近的通过鉴定子宫内膜中 RPLP1 蛋白的过度表达，观察结果进一步为该领域做出了贡献来自患有子宫内膜异位症、子宫腺肌病和子宫内膜癌的女性的上皮细胞。本期初步数据应用进一步表明 RPLP1 过度表达也可能影响孕酮的表达受体和孕激素信号传导。这是一个有趣的观察结果，子宫内膜异位症、子宫腺肌病和子宫内膜癌的特点都是孕激素抵抗。为了扩展这些新颖的观察结果，我们将检验子宫内膜上皮细胞 RPLP1 过度表达导致改变的具体假设子宫内膜上皮细胞分子谱与增殖、迁移和/或侵袭增强一致上皮间质转化（EMT）以及孕酮信号传导。为了检验这个假设，需要两个提出了具体目标，两者都利用了一种新的体内动物模型来实现 Rplp1 在子宫内膜上皮细胞。具体目标我将辨别上皮 Rplp1 的过度表达是否会导致受损女性生育能力、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 将询问细胞成分和由上皮 Rplp1 过度产生的新子宫分子途径表达。总的来说，本次拨款申请中提出的实验将为该角色提供新的见解 RPLP1 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发展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症。