Role of Membrane Estrogen Receptor 1 in Uterine Epithelial Response to Estrogen
Role of Membrane Estrogen Receptor 1 in Uterine Epithelial Response to Estrogen
批准号:
9316253
负责人:
Paul S. Cooke
金额:
$21.17万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-04-01 至 2019-03-31
关键词:
1-Phosphatidylinositol 3-KinaseAnimal ModelAnimalsAttenuatedBiologyCell NucleusCell ProliferationCell membraneCellsClinicalCytoplasmDataDevelopmentESR1 geneEndocrineEndocrinologyEndometrial CarcinomaEpithelialEstradiolEstrogen Nuclear ReceptorEstrogen Receptor alphaEstrogen ReceptorsEstrogensEventFemaleFertilityGenesGoalsGrowthHumanImpairmentInfertilityLigandsMediatingMediator of activation proteinMembraneMitogen-Activated Protein KinasesModelingMusNuclearNuclear EnvelopePartner in relationshipPathologic ProcessesPathologyPathway interactionsPhosphorylationPhysiologicalPhysiologyPlayProcessProtein KinaseProtein Tyrosine KinasePublished CommentRecruitment ActivityRegulationReproductionResearchRoleSignal TransductionSiteSteroidsStimulation of Cell ProliferationTestingTimeTissuesTransgenesTransgenic MiceTransgenic ModelTransgenic OrganismsUterusWorkbaseclinically significantendometriosisexperimental studyhuman diseaseimplantationinsightmalignant breast neoplasmmouse modelnovelreceptorreproductivereproductive tractresponsesteroid hormonetooltranscription factor
中文摘要
项目总结
英文摘要
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.
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Cell Fate Determination in Fetal Testes
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资助金额:$35.96万
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批准号:7735462
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资助金额:$37.4万
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财政年份:2009
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依托单位:
DIETARY PHYTOESTROGENS AND ADIPOCYTE DEVELOPMENT
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批准号:6856238
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资助金额:$26.02万
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Genistein induces thymic atrophy: a health concern?
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资助金额:$24.95万
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财政年份:2003
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依托单位:
Genistein induces thymic atrophy: a health concern?
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批准号:6748608
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项目类别:
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资助金额:$24.6万
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财政年份:2003
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依托单位:
Genistein induces thymic atrophy: a health concern?
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批准号:7049476
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资助金额:$23.57万
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财政年份:2003
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依托单位:
Genistein induces thymic atrophy: a health concern?
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财政年份:2003
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负责人:Paul S. Cooke
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依托单位:
MECHANISM OF ESTROGEN ACTION IN UTERUS AND VAGINA
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批准号:6055480
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项目类别:
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资助金额:$14.96万
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财政年份:1997
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负责人:Paul S. Cooke
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依托单位:
MECHANISM OF ESTROGEN ACTION IN UTERUS AND VAGINA
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批准号:2769449
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财政年份:1997
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依托单位:
MECHANISM OF ESTROGEN ACTION IN UTERUS AND VAGINA
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批准号:2624055
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资助金额:$15.53万
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财政年份:1997
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依托单位:
MECHANISM OF ESTROGEN ACTION IN UTERUS AND VAGINA
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批准号:6169206
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项目类别:
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资助金额:$15.37万
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财政年份:1997
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负责人:Paul S. Cooke
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依托单位:
CONTROL OF SERTOLI CELL PROLIFERATION
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财政年份:1992
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依托单位:
CONTROL OF SERTOLI CELL PROLIFERATION
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批准号:2201781
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-
财政年份:1992
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负责人:Paul S. Cooke
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依托单位:
CONTROL OF SERTOLI CELL PROLIFERATION
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财政年份:1992
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负责人:Paul S. Cooke
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依托单位:
海外基金