Mechanisms of PGRMC1 Action in Endometrial Proliferation

PGRMC1 在子宫内膜增殖中的作用机制

• 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
• 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

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.

项目总结/摘要 PGRMC 1在人子宫内膜中以最高水平表达，在雌激素主导的增殖期， 阶段，这表明这种相对未表征的蛋白质的功能，以协调上皮细胞增殖。 我们的实验室最近将鼠Pgrmc 1基因固定在一起，以评估该基因在背景中的功能。 女性生育能力的证据使用Pgr-cre小鼠进行的条件诱变研究表明，PGRMC 1对于 几种生长因子的表达和随后的上皮细胞增殖对雌二醇的反应 （E2）。例如，IGF-1是一种在子宫内膜间质中产生的生长因子， E2又与上皮细胞上的同源受体结合， 增殖基于这些新的发现，本申请的中心假设是PGRMC 1是 E2诱导的子宫内膜上皮细胞增殖和PGRMC 1的过度表达所必需的E2- 诱导子宫内膜增殖反应。一个可能的和预期的后果PGRMC 1超过- 表达是促进发育和进展的生长因子的产生增加 子宫内膜癌事实上，流行病学研究支持这样一种观点，即成年人的高体重 指数，导致全身雌酮升高，和绝经后激素替代疗法， 特别是长时间服用无对抗性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分子机制， PGRMC 1在调节E2信号转导和产生旁分泌生长因子中起作用， 促进子宫内膜增生。鉴定PGRMC 1相互作用蛋白是一个中心目标，这将 帮助建立PGRMC 1作用机制。对雌二醇（E2）信号的基本理解是 对于促进生殖生物学和发展战略，以打击过度增殖 子宫内膜疾病，如子宫内膜异位症和子宫内膜癌。