Role of Membrane Estrogen Receptor 1 in Uterine Epithelial Response to Estrogen

膜雌激素受体 1 在子宫上皮对雌激素反应中的作用

• 批准号: 9316253
• 负责人: Paul S. Cooke
• 金额: $ 21.17万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316253
• 关键词: 1-Phosphatidylinositol 3-Kinase; Animal Model; Animals; Attenuated; Biology; Cell Nucleus; Cell Proliferation; Cell membrane; Cells; Clinical; Cytoplasm; Data; Development; ESR1 gene; Endocrine; Endocrinology; Endometrial Carcinoma; Epithelial; Estradiol; Estrogen Nuclear Receptor; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Event; Female; Fertility; Genes; Goals; Growth; Human; Impairment; Infertility; Ligands; Mediating; Mediator of activation protein; Membrane; Mitogen-Activated Protein Kinases; Modeling; Mus; Nuclear; Nuclear Envelope; Partner in relationship; Pathologic Processes; Pathology; Pathway interactions; Phosphorylation; Physiological; Physiology; Play; Process; Protein Kinase; Protein Tyrosine Kinase; Published Comment; Recruitment Activity; Regulation; Reproduction; Research; Role; Signal Transduction; Site; Steroids; Stimulation of Cell Proliferation; Testing; Time; Tissues; Transgenes; Transgenic Mice; Transgenic Model; Transgenic Organisms; Uterus; Work; base; clinically significant; endometriosis; experimental study; human disease; implantation; insight; malignant breast neoplasm; mouse model; novel; receptor; reproductive; reproductive tract; response; steroid hormone; tool; transcription factor

Project Summary 17β-Estradiol (E2) controls uterine growth and receptivity at the time of implantation, and also plays major roles in development and progression of human diseases such as breast and endometrial cancer and endometriosis. Major E2 effects are primarily mediated through estrogen receptor 1 (ESR1). Most ESR1 is nuclear, but 5-10% is located in cell membranes. Understanding how E2 induces its actions and relative roles of nuclear and membrane ESR1 (nESR1 and mESR1, respectively) in both normal physiology and pathology is an important goal in steroid endocrinology. Dr. Levin from our group has developed two unique and powerful mouse models, the nuclear-only ESR1 (NOER) mouse, which lacks mESR1 but retains nESR1, and the membrane-only ESR1 (MOER) mouse, which expresses mESR1, but lacks nESR1. Critically, female NOER mice are infertile, with extensive reproductive abnormalities, and E2 stimulation of uterine epithelial proliferation is impaired in these animals. This led to the unexpected conclusion that mESR1 and nESR1 must work in concert to allow normal E2 regulation of uterine epithelial proliferation and other parameters, and suggests that the classical model of estrogen action focusing on nESR1 is not totally correct. Our long-term goal is to use NOER and MOER mice to define how mESR1 and nESR1 work together to mediate E2-induced uterine epithelial mitogenesis and other E2 effects. The objective of this research is to compare E2-induced uterine epithelial proliferation in ovariectomized WT and NOER mice to determine the specific aspects of nESR1 signaling that may be impaired by lack of mESR1. Identifying differences in E2 responses of WT and NOER uteri will allow us to determine the critical role(s) of mESR1 in facilitating nESR1 signaling to allow E2-induced epithelial proliferation. Extensive evidence suggests that mESR1 effects are mediated through the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, and downstream events induced by this signaling may be critical for mESR1 effects. This work will also determine the relative roles of the MAPK and PI3K pathways in mESR1 action. Finally, we have developed a compound transgenic mouse to determine if the truncated mESR1 used to develop the MOER mouse can rescue the fertility and other deficits in E2 signaling in the NOER mouse. Our overall hypothesis is that mESR1, acting through protein kinases, is critical for one or more steps in the nESR1 signaling cascade initiated by E2, and that the truncated mESR1 used to develop MOER mice will be capable of restoring fertility and E2 responsiveness in NOER mice. Proposed experiments will test this hypothesis and provide new and important information regarding nESR1 and mESR1's roles in mitogenic and other effects of E2. These experiments will provide a mechanistic basis for understanding the role of mESR1 in one of the most critical uterine effects of E2, and delineate how mESR1 facilitates normal E2/nESR1 signaling. These results have the potential to be iconoclastic and literally change our model of steroid hormone action developed over the past half century, and also have clinical significance for female reproductive pathologies.

项目摘要 17-雌二醇(17β-Estradiol，E_2)在着床时控制着子宫的生长和容受性，也起着重要作用 在人类疾病的发展和进展中，如乳腺癌、子宫内膜癌和子宫内膜异位症。 雌激素的主要作用主要是通过雌激素受体1(ESR1)介导的。大多数ESR1是核能，但5%-10% 位于细胞膜中。了解雌二醇如何诱导其作用及其与核相关的作用 膜ESR1(分别为nESR1和mESR1)在正常生理和病理中都是重要的 目标是类固醇内分泌学。我们团队的莱文博士开发了两种独特而强大的小鼠模型， 只有核的ESR1(NOER)小鼠，缺少mESR1但保留nESR1，以及只有膜的ESR1 (MOER)小鼠，表达mESR1，但缺乏nESR1。关键的是，雌性NOER小鼠是不育的， 在这些患者中，广泛的生殖异常和E2刺激子宫上皮细胞增殖的作用受损 动物。这导致了出人意料的结论，即mESR1和nESR1必须协同工作才能正常运行 E_2对子宫上皮细胞增殖的调节等参数，并提示经典模型 雌激素对nESR1的作用并不完全正确。我们的长期目标是使用NOER和MOER小鼠 明确mESR1和nESR1如何共同作用于介导E2诱导的子宫上皮有丝分裂及其他 雌二醇的影响。本研究的目的是比较雌激素诱导的子宫上皮细胞增殖。 切除卵巢的WT和NOER小鼠以确定可能受损的nESR1信号的特定方面 由于缺乏mESR1。识别WT和NOER子宫对E2反应的差异将使我们能够确定 MESR1在促进nESR1信号转导中的关键作用(S)，以允许E2诱导的上皮细胞增殖。广泛性 有证据表明，mESR1的作用是通过磷脂酰肌醇-3-激酶(PI3K)和 丝裂原活化蛋白激酶(MAPK)通路，以及由该信号诱导的下游事件可能是 对mESR1效应至关重要。这项工作还将确定MAPK和PI3K通路在 MESR1操作。最后，我们开发了一只复合转基因小鼠来确定截短的mESR1 用来发育MOER的小鼠可以挽救NOER小鼠的生育能力和其他E2信号的缺陷。 我们的总体假设是，mESR1通过蛋白激酶发挥作用，对大脑中的一个或多个步骤至关重要。 NESR1信号级联由E2启动，用于发育更多小鼠的截短mESR1将是 能够恢复NOER小鼠的生育能力和E2反应。拟议中的实验将检验这一点 并提供了有关nESR1和mESR1的S在促有丝分裂和细胞分裂中的作用的新的重要信息 雌二醇的其他作用。这些实验将为理解mESR1在体内的作用提供机制基础。 E2最关键的子宫效应之一，并描绘了mESR1如何促进正常的E2/nESR1信号转导。 这些结果有可能打破传统，并从字面上改变我们的类固醇激素作用模式 在过去的半个世纪里发展起来的，对女性生殖病理也有临床意义。