Estrogen receptor mediated reprogramming of prostate in BPH
BPH 中雌激素受体介导的前列腺重编程
基本信息
- 批准号:10224181
- 负责人:
- 金额:$ 50.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-15 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAgingAttenuatedAutomobile DrivingBenignBenign Prostatic HypertrophyCell CountCell NucleusCell ProliferationCell membraneChronic ProstatitisCyclic AMP-Dependent Protein KinasesDataDevelopmentDiethylstilbestrolDiseaseDisease susceptibilityESR1 geneEpigenetic ProcessEpithelialEstradiolEstrogen Nuclear ReceptorEstrogen Receptor alphaEstrogen ReceptorsEstrogensEventExhibitsExposure toFertilityFutureGene ExpressionGenesGenomicsGlandGoalsGrowthHealthHistologicHistonesHormonesHumanHyperplasiaImpairmentKnock-in MouseKnowledgeLeadLifeLigand BindingMAP Kinase GeneMediatingMembraneMemoryModelingModificationMolecularMusMutationNeonatalNuclearOrganPathologyPathway interactionsPhenotypePredisposing FactorPregnancyProstateProstaticProstatic EpitheliumProstatic hypertrophyPublishingRattusReportingReproductionResearchRodentRoleSignal PathwaySignal TransductionStructureTestingTransferaseTransgenic MiceWithdrawalWorkadenomabisphenol Aclinically relevantclinically significantcritical developmental perioddrug discoveryepigenomicsepithelial stem cellestrogenichistone methylationimprintinnovationinsightmalemouse modelnon-genomicpromoterprostate lesionsreceptorreproductivereproductive developmentreproductive tractresponsestemstem cellsxenoestrogen
项目摘要
ESTROGEN RECEPTOR MEDIATED REPROGRAMMING OF THE PROSTATE IN BPH
Paul S. Cooke and Gail S Prins, Multi-PIs
Abstract
Exposure to estrogens during critical developmental periods can permanently reprogram the prostate
gland, resulting in growth abnormalities in adult life that include stromal and epithelial hyperplasia, benign
adenomas and chronic prostatitis. As such, we propose that early-life estrogenic exposures may be a
predisposing factor for benign prostatic hyperplasia (BPH) in aging males. Past work has established that
epigenetic modifications underpin developmental reprogramming of the prostate; however, the pathways that
lead to this epigenomic reorganization are unclear. We previously showed that estrogen receptor 1 (ESR1;
also known as ERα) is essential and sufficient for this reprogramming; however, distinct signaling pathways
initiated through membrane ESR1 (mESR1) or nuclear ESR1 (nESR1) actions have not been clarified. Our
new published and preliminary data now reveal essential roles for mESR1 in normal male reproductive
development and fertility, as well as the normal prostatic response to developmental estrogenization. Further, a
recent report found that important epigenetic changes that could lead to hyperresponsivity of certain genes
involved in growth and cell proliferation can be initiated through mESR1 signaling cascades in the developing
prostate gland. In this context, the goals of the proposed research are to delineate relative roles of mESR1 and
nESR1 in mediating developmental estrogen reprogramming and to identify “nongenomic” pathways utilized by
mESR1 to reprogram epigenomic memory within the gland, including prostate epithelial stem cells. Herein, we
will take an innovative approach to directly interrogate mESR1 and nESR1 actions by utilizing newly developed
knock-in mouse models that express nESR1 normally but lack mESR1 signaling (nuclear-only ESR1 mouse;
NOER) or that express mESR1 and its downstream signaling pathways but lack nESR1 (H2NES mouse).
These powerful and unique new models allow us to take a direct experimental approach to tease out the
specific role(s) for ESR1 in each compartment and their downstream effectors on epigenetic imprinting in the
prostate, which has previously not been possible. Three Specific Aims are proposed to accomplish these
goals. Aim 1: Establish whether mESR1 is necessary and/or sufficient for estrogen-driven developmental
prostate reprogramming. Aim 2: Identify signaling cascades involved in estrogen-induced epigenetic imprinting.
Aim 3: Elucidate the roles of mESR1 and nESR1 in reprogramming prostate stem/progenitor cells. The
proposed studies will fill knowledge gaps on the differential roles of mESR1 and nESR1 in prostate
development and broaden the mechanistic basis for estrogenic imprinting in the prostate. Together, the results
will provide new and clinically relevant insights regarding the role of estrogen signaling through both mESR1
and nESR1 in driving BPH and inform future drug discovery strategies that can target membrane-initiated
estrogen signaling in the prostate.
前列腺增生中雌激素受体介导的前列腺重编程
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Role for Nongenomic Estrogen Signaling in Male Fertility.
非基因组雌激素信号在男性生育力中的作用。
- DOI:10.1210/endocr/bqad180
- 发表时间:2024
- 期刊:
- 影响因子:4.8
- 作者:Graceli,JonesB;Zomer,HelenaD;Medrano,TheresaI;Hess,RexA;Korach,KennethS;Cooke,PaulS
- 通讯作者:Cooke,PaulS
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Paul S. Cooke其他文献
Uterine-specific emEzh2/em deletion enhances stromal cell senescence and impairs placentation, resulting in pregnancy loss
子宫特异性 emEzh2/em 缺失会增强基质细胞衰老并损害胎盘形成,从而导致妊娠丢失
- DOI:
10.1016/j.isci.2023.107028 - 发表时间:
2023-07-21 - 期刊:
- 影响因子:4.100
- 作者:
Vijay K. Sirohi;Theresa I. Medrano;Athilakshmi Kannan;Indrani C. Bagchi;Paul S. Cooke - 通讯作者:
Paul S. Cooke
Understanding the role of thyroid hormone in Sertoli cell development: a mechanistic hypothesis
- DOI:
10.1007/s00441-005-1082-z - 发表时间:
2005-04-23 - 期刊:
- 影响因子:2.900
- 作者:
Denise R. Holsberger;Paul S. Cooke - 通讯作者:
Paul S. Cooke
Paul S. Cooke的其他文献
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{{ truncateString('Paul S. Cooke', 18)}}的其他基金
Steroid Hormone Pathways Regulating BPH and LUTS
调节 BPH 和 LUTS 的类固醇激素途径
- 批准号:
10601867 - 财政年份:2023
- 资助金额:
$ 50.48万 - 项目类别:
Estrogen receptor mediated reprogramming of prostate in BPH
BPH 中雌激素受体介导的前列腺重编程
- 批准号:
10002225 - 财政年份:2018
- 资助金额:
$ 50.48万 - 项目类别:
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 - 财政年份:2017
- 资助金额:
$ 50.48万 - 项目类别:
Membrane estrogen receptor 1 mediation of epigenetic effects of estrogen
膜雌激素受体1介导雌激素的表观遗传效应
- 批准号:
9182526 - 财政年份:2016
- 资助金额:
$ 50.48万 - 项目类别:
Membrane estrogen receptor 1 mediation of epigenetic effects of estrogen
膜雌激素受体1介导雌激素的表观遗传效应
- 批准号:
9401825 - 财政年份:2016
- 资助金额:
$ 50.48万 - 项目类别:
DIETARY PHYTOESTROGENS AND ADIPOCYTE DEVELOPMENT
膳食植物雌激素和脂肪细胞发育
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6856238 - 财政年份:2004
- 资助金额:
$ 50.48万 - 项目类别:
Genistein induces thymic atrophy: a health concern?
金雀异黄素会引起胸腺萎缩:健康问题吗?
- 批准号:
6868236 - 财政年份:2003
- 资助金额:
$ 50.48万 - 项目类别:
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