Mechanisms of PGRMC1 Action in Endometrial Proliferation

PGRMC1 在子宫内膜增殖中的作用机制

基本信息

批准号：
9182394
负责人：
James K Pru
金额：
$ 19万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-29 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9182394
关键词：
Address Adult Antral Binding Body mass index Cattle Cell Cycle Collaborations Connecticut Contraceptive Agents DTR gene Development Disease Endometrial Endometrial Carcinoma Endometrium Epidemiologic Studies Epithelial Cell Proliferation Epithelial Cells Estradiol Estrogens Estrone FGF1 gene Female Fertility Future Genes Goals Gonadal Steroid Hormones Growth Health Human Hysterectomy Insulin-Like Growth Factor I Knock-out Knockout Mice Link Longevity LoxP-flanked allele Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mediating Membrane Molecular Monkeys Mus Mutagenesis Mutant Strains Mice Operative Surgical Procedures Outcome Ovarian Ovulation PTEN gene Pattern Pharmaceutical Preparations Phase Physiological Play Post-Menopausal Hormone Replacement Therapy Premature Ovarian Failure Prevalence Production Progesterone Receptors Proteins Proteomics Proto-Oncogene Proteins c-akt Rat-1 Reagent Regulation Regulator Genes Reproductive Biology Risk Factors Role Severities Signal Transduction Solid Syndrome Testing Time Tissues Universities Uterus Validation Woman Work abstracting base cancer cell clinically relevant combat design endometriosis gene function gene therapy granulosa cell infertility treatment mRNA Expression malignant breast neoplasm novel overexpression paracrine practical application protein function receptor reproductive reproductive function response transcriptome sequencing tumor tumor xenograft

项目摘要

Project Summary/Abstract PGRMC1 is expressed in the human endometrium at highest levels during the estrogen dominated proliferative phase, suggesting that this relatively uncharacterized protein functions to coordinate epithelial cell proliferation. Our lab recently floxed the murine Pgrmc1 gene in an effort to evaluate the function of this gene in the context of female fertility. Conditional mutagenesis studies using Pgr-cre mice revealed that PGRMC1 is necessary for the expression of several growth factors and subsequent epithelial cell proliferation in response to estradiol (E2). IGF-1, for example, is well-established as a growth factor produced in the endometrial stromal compartment in response to E2 that in turn binds to its cognate receptor on epithelial cells and drives proliferation. Based on these novel findings, the central hypothesis of this application is that PGRMC1 is essential for E2-induced endometrial epithelial cell proliferation and over-expression of PGRMC1 elevates E2- induced proliferative responses in the endometrium. A likely and expected consequence of PGRMC1 over- expression is the elevated production of growth factors that would promote development and progression toward endometrial cancer. Indeed, epidemiological studies support the concept that high adult body mass index, which results in elevated systemic estrone, and postmenopausal hormone replacement therapy, particularly unopposed E2 taken for an extended period of time, are solid risk factors for Type 1 E2-dependent endometrial cancers. The goal of this application is to investigate the molecular mechanisms by which PGRMC1 functions in the regulation of E2 signal transduction and production of paracrine growth factors that promote endometrial proliferation. Identifying PGRMC1-interacting proteins is a central objective and this will help establish PGRMC1 mechanism of action. A fundamental understanding of how estradiol (E2) signals is necessary for advancing reproductive biology and for developing strategies to combat hyperproliferative diseases of the endometrium such as endometriosis and endometrial cancer.

项目概要/摘要 PGRMC1 在雌激素主导的增殖期在人类子宫内膜中表达最高水平相，表明这种相对未表征的蛋白质具有协调上皮细胞增殖的功能。我们的实验室最近对小鼠 Pgrmc1 基因进行了固定，以评估该基因在背景下的功能女性生育能力。使用 Pgr-cre 小鼠进行的条件诱变研究表明，PGRMC1 对于几种生长因子的表达以及随后对雌二醇的反应的上皮细胞增殖（E2）。例如，IGF-1 被认为是子宫内膜基质中产生的生长因子区室响应 E2，而 E2 又与其上皮细胞上的同源受体结合并驱动增殖。基于这些新发现，本申请的中心假设是 PGRMC1 是对于 E2 诱导的子宫内膜上皮细胞增殖至关重要，PGRMC1 的过度表达会升高 E2- 诱导子宫内膜增殖反应。 PGRMC1 过度的可能和预期后果表达是促进发育和进展的生长因子产量的增加走向子宫内膜癌。事实上，流行病学研究支持成人高体重这一概念指数，导致全身雌酮升高，以及绝经后激素替代疗法，特别是长时间服用不受阻碍的 E2，是 1 型 E2 依赖性的可靠风险因素子宫内膜癌。本申请的目的是研究其分子机制 PGRMC1 在调节 E2 信号转导和旁分泌生长因子的产生中发挥作用促进子宫内膜增殖。识别 PGRMC1 相互作用蛋白是一个中心目标，这将帮助建立PGRMC1的作用机制。对雌二醇 (E2) 信号如何产生的基本了解对于推进生殖生物学和制定对抗过度增殖的策略是必要的子宫内膜疾病，例如子宫内膜异位症和子宫内膜癌。