Gender Bias in Gastrointestinal Motility in Health and Diabetes
健康和糖尿病中胃肠动力的性别偏见
基本信息
- 批准号:10581703
- 负责人:
- 金额:$ 37.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-17 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAgonistAnimal ModelAutonomic nervous systemBindingColonConstipationCoupledCyclic AMPCyclic AMP-Dependent Protein KinasesCyclic GMPDataDevelopmentDiabetes MellitusDiabetic mouseDiestrusDown-RegulationEstrogen Receptor alphaEstrogen Receptor betaEstrogensEstrusEtiologyEventExhibitsFemaleGPER geneGastrointestinal MotilityGastrointestinal TransitGastroparesisGoalsHealthHistone AcetylationHistone DeacetylaseHistone H3HomeostasisHormonal ChangeImpairmentKnockout MiceKnowledgeLysineMediatingMembraneMenstrual cycleMethylationMolecularMusMuscle functionMuscle relaxation phaseNeuronsNuclear ReceptorsObesityOxidative StressOxidative Stress InductionPathway interactionsPatternPeripheralPhasePregnancyPrevalenceProestrusPromoter RegionsProtein IsoformsPublic HealthReceptor GeneRegulationRelaxationReportingResearch ProposalsRoleSTIM1 geneSerotoninSex BiasSignal PathwaySignal TransductionSmooth MuscleStomachTestingVascular Smooth MuscleWomanchromatin immunoprecipitationclinically significantdifferential expressionepigenetic regulationgastrointestinalinsightmalemenmotility disordernovel therapeuticspromoterreceptor expressionresponseselective expressionsexsexual dimorphismtranscriptome sequencing
项目摘要
Gastrointestinal (GI) motility is sexually dimorphic. In women, GI motility varies with hormonal changes
during the menstrual cycle and pregnancy. However, there is a gap in the knowledge and understanding the
role of estrogen and the mechanism by which it regulates sex- and cycle-dependent changes in GI motility and
dysmotility. Unlike classical nuclear receptors ERα, ERβ, activation of membrane-bound G protein-coupled
estrogen receptor (GPER) by estrogen initiates rapid cellular events. We have obtained preliminary evidence to
show that GPER is expressed in smooth muscle and is coupled to AC/cAMP/PKA pathway to mediate muscle
relaxation in the stomach and the colon. Smooth muscle from GPER KO mice exhibited loss of relaxation in
response to GPER agonist providing evidence for a role of GPER in smooth muscle relaxation. GI transit was
delayed in female mice of high-estrogen proestrus and estrus phases compared to low-estrogen diestrus phase,
and male mice. These sex- and cycle-dependent changes in GI transit are associated with changes in the
expression and function of GPER. Based on these preliminary data, studies are proposed to test the hypothesis
that sex- and cycle-dependent changes in GI transit are due to changes in expression and function of GPER
coupled to activation of AC/cAMP/PKA pathway and smooth muscle relaxation (Specific Aim 1).
GI motility disorders are also sexually dimorphic. There is greater prevalence of diabetes-associated
gastroparesis and constipation in women compared to men. The contribution of impaired smooth muscle function
and role of GPER in smooth muscle has not been fully explored in sexual dimorphism in GI dysmotility in
diabetes. Preliminary studies showed that expression of GPER was decreased in smooth muscle from diabetic
mice and the decrease is mediated via oxidative stress-induced changes in epigenetic regulation via a decrease
in trimethylation of H3 at lysine residue 4 (H3K4me3) and acetylation of H3 at lysine residue 27 (H3K27ac) at
the promoter region of GPER gene. RNA-seq data combined with heatmap analysis showed an increase in the
expression of selective histone deacetylase (HDACs) in smooth muscle from diabetic mice. An increase in
oxidative stress was also obtained in smooth muscle from GPER KO mice suggesting the increase in oxidative
stress in diabetes could be due to a decrease in GPER expression. Based on the preliminary data, studies ae
proposed to test the hypothesis that an increase in oxidative stress in diabetes downregulates GPER expression
via decrease in H3K4me3 and H3K27ac of GPER promoter, and loss of GPER-mediated protection against
oxidative stress leads to decrease in cAMP/cGMP signaling, muscle relaxation and GI transit (Specific Aim 2).
Knowledge gained from our study is intended to provide insights into the cellular mechanisms involved
in sex-and cycle-dependent changes in GI motility. The unknown underlying etiology of female sex-specific
prominence of diabetes-associated GI dysmotility underscores the clinical significance of the proposed studies.
胃肠道(GI)运动是两性异形的。在女性中,胃肠道动力随激素变化而变化
在月经周期和怀孕期间。然而,在知识和理解方面存在差距,
雌激素的作用及其调节GI运动性和周期依赖性变化的机制,
运动障碍与经典的核受体ERα、ERβ不同,
雌激素受体(GPER)通过雌激素启动快速细胞事件。我们已经获得了初步证据,
显示GPER在平滑肌中表达,并与AC/cAMP/PKA途径偶联以介导肌肉
胃和结肠的松弛来自GPER KO小鼠的平滑肌表现出松弛损失,
对GPER激动剂的反应,为GPER在平滑肌松弛中的作用提供了证据。GI运输是
与低雌激素间情期相比,高雌激素雌性小鼠的动情前期和动情期延迟,
和雄性小鼠。这些性别和周期依赖性的胃肠道转运变化与胃肠道的变化有关。
GPER的表达和功能。基于这些初步的数据,研究提出了检验假设
性别和周期依赖性的胃肠道转运变化是由于GPER表达和功能的变化
偶联AC/cAMP/PKA通路的激活和平滑肌松弛(特异性目的1)。
胃肠道动力障碍也是性二态性的。与糖尿病相关的
胃轻瘫和便秘。受损的平滑肌功能
GPER在平滑肌中的作用在胃肠道动力障碍的性二型性中还没有得到充分的研究,
糖尿病初步研究表明,糖尿病大鼠血管平滑肌GPER表达降低,
小鼠和减少是介导的氧化应激诱导的变化,表观遗传调节,通过减少
在赖氨酸残基4处H3的三甲基化(H3 K4 me 3)和在赖氨酸残基27处H3的乙酰化(H3 K27 ac)中,
GPER基因启动子区。RNA-seq数据结合热图分析显示,
糖尿病小鼠平滑肌中选择性组蛋白脱乙酰酶(HDAC)的表达。增加
在GPER KO小鼠的平滑肌中也获得了氧化应激,这表明氧化应激的增加。
糖尿病中应激可能是由于GPER表达减少。根据初步数据,
为了检验糖尿病中氧化应激的增加下调GPER表达的假设,
通过GPER启动子的H3 K4 me 3和H3 K27 ac的减少,以及GPER介导的抗
氧化应激导致cAMP/cGMP信号传导、肌肉松弛和GI转运的减少(具体目标2)。
从我们的研究中获得的知识旨在提供有关细胞机制的见解
在性别和周期依赖性变化的胃肠道运动。女性性别特异性的潜在病因不明
糖尿病相关胃肠道动力障碍的突出强调了拟议研究的临床意义。
项目成果
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