Obesity-driven endometrial hyperplasia in postmenopausal women: Synergistic role for insulin and estrone
绝经后妇女肥胖导致的子宫内膜增生:胰岛素和雌酮的协同作用
基本信息
- 批准号:10593167
- 负责人:
- 金额:$ 42.04万
- 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:2019-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AgeArchitectureAtypical Endometrial HyperplasiasBenignBody Weight decreasedBody mass indexBreast Cancer TreatmentCase/Control StudiesChronicClinical ManagementDataDevelopmentDiabetes MellitusEndometrialEndometrial CarcinomaEndometrial HyperplasiaEndometrial adenocarcinomaEndometriumEnrollmentEstradiolEstrogen Receptor alphaEstrogen Receptor betaEstrogen ReceptorsEstrogensEstroneFrequenciesGPER geneGene ExpressionGene Expression ProfileGenomicsGlandGrowthGrowth FactorHistologicHistologyHormonesHumanHyperinsulinismHyperplasiaInflammationInsulinInsulin ReceptorInsulin Signaling PathwayKnock-outLesionLigandsMalignant NeoplasmsMeasuresMediatingMenopauseMetabolicMetabolic hormoneModelingMorbid ObesityMusNon-Insulin-Dependent Diabetes MellitusNuclear AtypiaObesityObesity EpidemicOutcomeOvarianOvaryOverweightPathway interactionsPatternPharmaceutical PreparationsPlacebosPostmenopausePrecancerous ConditionsPredispositionPreventionProcessProductionProgesteroneProgestinsProliferatingProtein IsoformsReceptor SignalingRegulationRelative RisksReportingResearchRisk FactorsRoleSeveritiesStimulation of Cell ProliferationTestingThinnessTimeTissue-Specific Gene ExpressionTissuesTransgenic OrganismsUterusWild Type MouseWithdrawalWomanWorkagedclinical phenotypeepidemiology studygenetic signaturehigh riskinsulin signalingmouse modelobesity developmentreceptorsynergismtimelinetranscriptome
项目摘要
PROJECT SUMMARY / ABSTRACT
Obesity-driven cancers are well described, and the highest risk is reported for endometrial cancer.
Epidemiological studies show an impressive escalation in endometrial adenocarcinoma (EC) as obesity severity
increases, with relative risks of 1.5, 2.5, 4.5 and 7.1 for overweight, moderate, severe and very severe obesity,
respectively. Rates of EC are rising with the obesity epidemic. EC has a precursor lesion, atypical endometrial
hyperplasia (AEH). While AEH has a high transformation rate of 30% to EC, AEH grows slowly, offering the
opportunity for prevention. However, we do not know why obesity promotes the development of AEH and EC.
This project proposes to investigate two pathways for the development of obesity-driven endometrial
hyperplasia in post-menopausal women. We hypothesize that pathophysiological levels of estrone promote
irregular gland architecture, whereas hyperinsulinemia promotes nuclear atypia in a synergistic process that
leads to atypical endometrial hyperplasia. In this project we will characterize changes in endometrial histology
and uterine gene expression that occur over time, in mice who have pathophysiological levels of insulin and
estrone, as occur in women with obesity. For confirmatory testing of hormone induced histology, we will use
established mouse models of estrogen receptor-α (ERα) and insulin receptor (IR) deletions. We will also
examine the histological effect of combined insulin and estrone stimulation in mice. Outcomes include a
timeline assessment of histological and gene expression changes toward AEH. Finally, we propose a case-
control study to elucidate whether insulin and estrone play a role in AEH development in post-menopausal
women. We intend to enroll 30 women with AEH and 30 women without AEH, who have severe obesity.
Circulating estrone and insulin levels will be measured, and endometrial tissue will be assessed for IR and ERα
expression levels as well as global gene expression. We will identify insulin and estrone patterns of gene
expression in AEH by comparing differential gene expression between AEH and benign endometrium to
differential gene expression of uteri from insulin &/or estrone exposed mice relative to their controls. The
immediate implications of this research may include opening the clinical management of AEH to the well-
established strategy of weight loss, insulin-lowering agents as used in the treatment of type 2 diabetes, and
estrone lowering agents as used in the treatment of breast cancer. The longer-term, broader implications of this
research are to understand the mechanisms for how obesity induced metabolic and hormone changes alter
susceptibility to many obesity-driven cancers.
项目摘要/摘要
项目成果
期刊论文数量(0)
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Clare Ann Flannery其他文献
Clare Ann Flannery的其他文献
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{{ truncateString('Clare Ann Flannery', 18)}}的其他基金
Obesity-driven endometrial hyperplasia in postmenopausal women: Synergistic role for insulin and estrone
绝经后妇女肥胖导致的子宫内膜增生:胰岛素和雌酮的协同作用
- 批准号:
10335193 - 财政年份:2019
- 资助金额:
$ 42.04万 - 项目类别:
Effect of Insulin on Estrogen Receptor Alpha Activity in Human Endometrial Cells
胰岛素对人子宫内膜细胞雌激素受体α活性的影响
- 批准号:
8883230 - 财政年份:2012
- 资助金额:
$ 42.04万 - 项目类别:
Effect of Insulin on Estrogen Receptor Alpha Activity in Human Endometrial Cells
胰岛素对人子宫内膜细胞雌激素受体α活性的影响
- 批准号:
8534800 - 财政年份:2012
- 资助金额:
$ 42.04万 - 项目类别:
Effect of Insulin on Estrogen Receptor Alpha Activity in Human Endometrial Cells
胰岛素对人子宫内膜细胞雌激素受体α活性的影响
- 批准号:
8691432 - 财政年份:2012
- 资助金额:
$ 42.04万 - 项目类别:
Effect of Insulin on Estrogen Receptor Alpha Activity in Human Endometrial Cells
胰岛素对人子宫内膜细胞雌激素受体α活性的影响
- 批准号:
8384143 - 财政年份:2012
- 资助金额:
$ 42.04万 - 项目类别:
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