Mechanisms of PGRMC1 Action in Endometrial Proliferation

项目摘要/摘要 前列腺素RMC1在雌激素控制的增殖期子宫内膜中的表达水平最高 这表明，这种相对未知的蛋白质具有协调上皮细胞增殖的功能。 我们实验室最近对小鼠的PGRMC1基因进行了筛选，以期在此背景下评估该基因的功能 女性的生育能力。用PGR-cre小鼠进行的条件突变研究表明，PGRMC1是 雌激素对几种生长因子表达及随后的上皮细胞增殖的影响 (2)。例如，IGF-1被公认为是子宫内膜间质中产生的一种生长因子。 与E2反应的隔室，进而与其上皮细胞上的同源受体结合并驱动 扩散。基于这些新发现，这一应用的中心假设是PGRMC1是 对E2诱导的子宫内膜上皮细胞增殖至关重要，PGRMC1的过度表达可促进E2- 诱导子宫内膜增殖性反应。PGRMC1过度的一个可能和预期的后果- 表达是促进发育和进展的生长因子的增加。 子宫内膜癌。事实上，流行病学研究支持这样一个概念，即成年人的高体重 导致全身雌酮升高的指数，以及绝经后激素替代疗法， 尤其是长期服用无抗药性的雌二醇组，是1型雌二醇性依赖症的可靠危险因素 子宫内膜癌。这项应用的目标是研究分子机制， 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。鉴定与PGRMC1相互作用的蛋白质是一个中心目标，这将 帮助建立PGRMC1行动机制。对雌二醇(E2)信号的基本了解 对于促进生殖生物学和制定对抗过度增殖的战略是必要的 子宫内膜疾病，如子宫内膜异位症和子宫内膜癌。

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.