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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 17β-雌二醇 (E2) 在着床时控制子宫生长和容受性，也发挥着重要作用乳腺癌、子宫内膜癌和子宫内膜异位症等人类疾病的发生和进展。主要的 E2 效应主要通过雌激素受体 1 (ESR1) 介导，大多数 ESR1 位于核内，但仅占 5-10%。了解 E2 如何诱导其作用以及细胞核和细胞膜的相关作用。膜ESR1（分别为nESR1和mESR1）在正常生理和病理中都是重要的我们小组的 Levin 博士开发了两种独特且强大的小鼠模型，仅核 ESR1 (NOER) 小鼠，缺乏 mESR1 但保留 nESR1，以及仅膜 ESR1 (MOER) 小鼠，表达 mESR1，但缺乏 nESR1 关键的是，雌性 NOER 小鼠不育，具有广泛的生殖异常，并且 E2 对子宫上皮增殖的刺激在这些情况下受损这导致了一个意想不到的结论：mESR1 和 nESR1 必须协同工作才能正常。 E2对子宫上皮增殖和其他参数的调节，并表明经典模型雌激素作用集中于 nESR1 并不完全正确我们的长期目标是使用 NOER 和 MOER 小鼠。定义 mESR1 和 nESR1 如何共同介导 E2 诱导的子宫上皮有丝分裂和其他本研究的目的是比较 E2 诱导的子宫上皮增殖。切除卵巢的 WT 和 NOER 小鼠以确定可能受损的 nESR1 信号传导的具体方面识别 WT 和 NOER 的 E2 反应差异将使我们能够确定 mESR1 在促进 nESR1 信号传导以允许 E2 诱导的上皮细胞广泛增殖中发挥关键作用。有证据表明 mESR1 效应是通过磷脂酰肌醇 3 激酶 (PI3K) 介导的丝裂原激活蛋白激酶（MAPK）途径，以及由该信号传导诱导的下游事件可能是这项工作还将确定 MAPK 和 PI3K 通路在 mESR1 效应中的相对作用。最后，我们开发了一种复合转基因小鼠来确定是否截短的mESR1。用于开发 MOER 小鼠可以挽救 NOER 小鼠的生育能力和 E2 信号传导的其他缺陷。我们的总体假设是，mESR1 通过蛋白激酶发挥作用，对于该过程中的一个或多个步骤至关重要。 nESR1信号级联由E2启动，并且用于开发MOER小鼠的截短的mESR1将被能够恢复 NOER 小鼠的生育能力和 E2 反应性。拟议的实验将对此进行测试。假说并提供有关 nESR1 和 mESR1 在促有丝分裂和 E2 的其他作用将为理解 mESR1 的作用提供机制基础。 E2 对子宫最重要的影响之一，并描述了 mESR1 如何促进正常的 E2/nESR1 信号传导。这些结果有可能打破传统并真正改变我们的类固醇激素作用模型近半个世纪以来的发展，对女性生殖病理学也具有临床意义。