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

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

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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.

项目摘要/摘要 PGRMC1在雌激素中以最高水平的增生为主的人子宫内膜中表达相位，表明这种相对未表征的蛋白质功能可以协调上皮细胞增殖。我们的实验室最近对鼠PGRMC1基因进行了努力，以评估该基因在上下文中的功能女性生育能力。使用PGR-CRE小鼠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上皮细胞增殖的表达（E2）。例如，IGF-1作为子宫基质中产生的生长因子的建立良好响应于E2的隔室又与其上皮细胞上的同源受体结合并驱动增殖。基于这些新颖的发现，该应用的中心假设是PGRMC1是对于E2诱导的子宫内膜上皮细胞增殖至关重要，PGRMC1的过表达升高E2- 子宫内膜中诱导的增生反应。 PGRMC1过度的可能和预期的结果表达是增长因子的产生升高，可以促进发展和发展迈向子宫内膜癌。实际上，流行病学研究支持了高成年体重的概念指数导致全身雌酮升高和绝经后激素替代疗法，特别是无反对的E2长期服用，是1型E2依赖性的固体风险因素子宫内膜癌。该应用的目的是研究分子机制 PGRMC1在E2信号转导和旁分泌生长因子的产生中起作用促进子宫内膜增殖。识别PGRMC1相互作用蛋白是一个核心目标，这将帮助建立PGRMC1作用机理。对雌二醇（E2）信号的基本了解推进生殖生物学和制定策略以对抗超增殖性超增强的必要子宫内膜疾病，例如子宫内膜异位症和子宫内膜癌。