Using Nonclassical Estrogen Signaling to Prevent Melanoma
使用非经典雌激素信号传导预防黑色素瘤
基本信息
- 批准号:10580032
- 负责人:
- 金额:$ 41.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAgonistCessation of lifeCyclic AMPCyclic AMP-Dependent Protein KinasesDNA DamageDNA RepairDNA Sequence AlterationDataDevelopmentDiagnosisDiseaseDrug TargetingEP300 geneEnzymesEpigenetic ProcessEstradiolEstrogen Nuclear ReceptorEstrogen Receptor alphaEstrogen ReceptorsEstrogensExposure toFamily history ofFemaleFutureG-Protein-Coupled ReceptorsGTP-Binding ProteinsGenderGeneticGenetic TranscriptionGenetically Engineered MouseGenome StabilityGravinGrowthHairHealthHistone AcetylationHistone DeacetylaseHistone Deacetylase InhibitorHistonesHumanImmunofluorescence ImmunologicImmunotherapyIn VitroIncidenceLigandsLightMalignant - descriptorMass Spectrum AnalysisMediatingMedicalMemoryMetastatic MelanomaModelingMusMutagenesisMutationNucleotide Excision RepairOncogenicOutcomePathway interactionsPatientsPersonsPharmaceutical PreparationsPhosphorylationPhysiologicalPregnancyPrevention strategyProliferatingProteinsReceptor ActivationReceptor SignalingRiskSignal InductionSignal TransductionSiteSkinSkin CancerSkin PigmentationSomatic MutationSouthwestern BlottingSun ExposureSurgical incisionsTestingTransferaseUV Radiation ExposureUV induced DNA damageWithdrawalWorkXPA geneadvanced diseaseantagonistcancer celleffective therapyepigenetic memoryestrophilinexome sequencingexperimental studyhigh riskhigh risk populationhistone acetyltransferaseimprovedin vivomalemelanocytemelanomamennovel therapeuticspharmacologicpreventprotective effectrecruitresponsesexskin xenografttargeted treatmenttherapeutic targettumortumor progressionultraviolet
项目摘要
Project summary: Despite advances in melanoma treatment, only 33% of patients with advanced
disease respond to the most effective therapy and mean survival is only 23 months. Millions of people
with red hair, or light skin pigmentation have an especially high melanoma risk. Although strategies to
decrease this risk are lacking, our recent discoveries suggest that melanoma incidence may be
diminished by pharmacologically activating the G-Protein Estrogen Receptor (GPER), a protein on
melanocytes with activity completely distinct from the classic estrogen receptor (ERα/β). Although there
are no approved drugs that target GPER, GPER is activated in melanocytes by a selective synthetic
compound (G-1) that does not have any classic estrogen activity. We recently determined that
pharmacologic GPER activation in vivo inhibits established melanomas, largely by inducing terminal
differentiation in cancer cells. Our preliminary studies now suggest that G-1 mediated GPER activation
in melanocytes induces long-term epigenetic changes that prevent future melanoma, while allowing
skin melanocytes to continue to function normally.
In Aim I we will use primary human melanocytes to determine the specific histone modifying enzymes
required for inducing epigenetic transcriptional memory that maintains a heightened state of cellular
differentiation after transient GPER activation, and test whether HDAC inhibition potentiates the
differentiation effects of the GPER agonist.
In Aim II we will validate preliminary results suggesting that GPER signaling induces pathways that
promote DNA repair, and thereby minimizes the accumulation of DNA mutations after ultraviolet (UV)
exposure. We will determine the mechanism(s) downstream of GPER that mediate the improved DNA
damage response, which may help highlight additional therapeutic targets.
In Aim III we will use both human and mouse melanoma models to directly test whether G-1
activation of GPER promotes DNA repair after UV exposure in vivo, and inhibits melanoma
development.
项目总结:尽管黑色素瘤治疗取得了进展,但只有33%的晚期黑色素瘤患者
对最有效的治疗有反应,平均生存期只有23个月。数百万人
红头发或浅色皮肤的人患黑色素瘤的风险特别高。虽然战略,
我们最近的发现表明,黑色素瘤的发病率可能是
雌激素受体(GPER)是一种蛋白质,
活性完全不同于经典雌激素受体(ERα/β)的黑素细胞。虽然
目前还没有批准的靶向GPER的药物,GPER在黑素细胞中被一种选择性合成的
化合物(G-1)不具有任何经典的雌激素活性。我们最近确定,
体内药理学GPER激活主要通过诱导终末
癌细胞的分化。我们的初步研究表明,G-1介导的GPER激活
在黑素细胞中诱导长期的表观遗传变化,防止未来的黑色素瘤,同时允许
皮肤黑色素细胞继续正常运作。
在目的I中,我们将使用原代人类黑素细胞来确定特定的组蛋白修饰酶
所需的诱导表观遗传转录记忆,保持高度状态的细胞
在瞬时GPER激活后,HDAC抑制是否增强了细胞的分化,
GPER激动剂的分化作用。
在目标II中,我们将验证初步结果,表明GPER信号转导诱导的途径,
促进DNA修复,从而最大限度地减少紫外线(UV)照射后DNA突变的积累
exposure.我们将确定GPER下游介导改善DNA的机制,
损伤反应,这可能有助于突出其他治疗靶点。
在Aim III中,我们将使用人类和小鼠黑色素瘤模型直接测试G-1是否
GPER的激活促进体内UV暴露后的DNA修复,并抑制黑素瘤
发展
项目成果
期刊论文数量(0)
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{{ truncateString('TODD W RIDKY', 18)}}的其他基金
Impact of Endogenous DOPA Signaling on Melanocyte Homeostasis and Melanoma Susceptibility
内源性多巴信号对黑色素细胞稳态和黑色素瘤易感性的影响
- 批准号:
10475365 - 财政年份:2021
- 资助金额:
$ 41.94万 - 项目类别:
Using Nonclassical Estrogen Signaling to Prevent Melanoma
使用非经典雌激素信号传导预防黑色素瘤
- 批准号:
10112838 - 财政年份:2019
- 资助金额:
$ 41.94万 - 项目类别:
Using Nonclassical Estrogen Signaling to Prevent Melanoma
使用非经典雌激素信号传导预防黑色素瘤
- 批准号:
10381619 - 财政年份:2019
- 资助金额:
$ 41.94万 - 项目类别:
Using Nonclassical Estrogen Signaling to Prevent Melanoma
使用非经典雌激素信号传导预防黑色素瘤
- 批准号:
9895651 - 财政年份:2019
- 资助金额:
$ 41.94万 - 项目类别:
Physiologic Function of RAS Effectors MEK 1/2 on Epidermal Differentiation
RAS效应器MEK 1/2对表皮分化的生理功能
- 批准号:
8131855 - 财政年份:2007
- 资助金额:
$ 41.94万 - 项目类别:
Physiologic Function of RAS Effectors MEK 1/2 on Epidermal Differentiation
RAS效应器MEK 1/2对表皮分化的生理功能
- 批准号:
7495164 - 财政年份:2007
- 资助金额:
$ 41.94万 - 项目类别:
Physiologic Function of RAS Effectors MEK 1/2 on Epidermal Differentiation
RAS效应器MEK 1/2对表皮分化的生理功能
- 批准号:
7664424 - 财政年份:2007
- 资助金额:
$ 41.94万 - 项目类别:
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