Epigenetic Mechanisms in Developmental Mismatch
发育不匹配的表观遗传机制
基本信息
- 批准号:9135636
- 负责人:
- 金额:$ 14.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-18 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAddressAdultAdverse effectsAffectAnimal ModelBioinformaticsBiologicalBiologyBirthBirth WeightBody WeightBrain regionControl GroupsDNADNA MethylationDataDatabasesDeveloped CountriesDevelopmentDietDietary SupplementationEatingEnergy MetabolismEnvironmental ExposureEpidemicEpigenetic ProcessExerciseExhibitsFaminesFemaleFetal Growth RetardationFosteringGrowthHealthHome environmentHumanHypothalamic structureIndividualInfantInterventionKnowledgeLeadMediatingMethylationModelingMolecularMusNeuraxisNeuronsNeurosciencesNutritionalObesityPerinatalPhysical activityPopulationPopulation HeterogeneityPredispositionPregnancyPreventionProcessRegulationResearchResearch PersonnelRiskSupplementationTestingTimeTissue BanksWeaningWomancritical perioddesigndevelopmental nutritiondietary supplementseffective interventionenergy balanceepidemiologic dataexperienceimprovedin uteromalenovelnutritionoffspringpostnatalpreventprogramssex
项目摘要
DESCRIPTION (provided by applicant): Nutritional influences during critical periods of development induce permanent changes in energy balance regulation. There is an urgent need to determine the extent to which such `developmental programming' of body weight regulation is exacerbating the worldwide obesity epidemic, but our understanding of the underlying biology remains rudimentary. The proposed research focuses on a new model of developmental mismatch (i.e. fetal growth restriction followed by postnatal catch-up growth): the agouti viable yellow (Avy) mouse. We will use this model to investigate fundamental epigenetic mechanisms in the central nervous system (CNS) that mediate developmental programming of energy balance. This proposal builds upon our recent discovery that offspring of Avy/a dams are growth restricted in utero, but undergo postnatal catch-up growth, and exhibit adult obesity only in females. This developmentally programmed difference in body weight regulation is mediated not by increased food intake but by persistent blunting of spontaneous physical activity. We propose to advance our understanding of developmental mismatch by achieving the following Aims: Aim 1: Determine if postnatal catch-up growth is required for programming of physical inactivity and obesity. Offspring of Avy/a mice experience fetal growth restriction, pointing to processes occurring in utero. It is unknown, however, whether catch-up growth during the suckling period is a required component of the `programming' mechanism. To test this, offspring of Avy/a dams will be fostered to a/a (wild type) dams in normal size or large litters to allow or prevent catch-growth during the suckling period, respectively. Aim 2: Determine if wild type offspring of Avy/a mice exhibit sex-specific, persistent alterations in DNA methylation in the CNS. Female wild type offspring of Avy/a dams exhibit persistently blunted spontaneous physical activity (home cage activity) and energy expenditure. We will test the hypothesis that these persistent changes are mediated by induced alterations in DNA methylation in the hypothalamus and other regions of the CNS. Aim 3: Test the hypothesis that dietary methyl donor supplementation of Avy/a dams normalizes physical activity in their female offspring by correcting CNS DNA methylation. We will test the hypothesis that a pro- methylation dietary supplement normalizes physical activity and adiposity in this model by preventing aberrant locus-specific DNA hypomethylation in the hypothalamus and other CNS regions in female offspring. Overall, these studies aim to elucidate the molecular mechanisms by which catch-up growth leads to persistent and female-specific alterations in body weight regulation. Understanding these cellular and molecular determinants may lead to effective approaches to prevent and treat human obesity.
描述(由申请人提供):发育关键时期的营养影响会导致能量平衡调节的永久性变化。迫切需要确定体重调节的这种“发育编程”在多大程度上加剧了世界范围内的肥胖流行,但我们对潜在生物学的理解仍然很初级。拟议的研究重点是一种新的发育不匹配模型(即胎儿生长受限,随后出生后追赶生长):刺豚鼠活黄色(Avy)小鼠。我们将使用该模型来研究中枢神经系统(CNS)中介导能量平衡发育编程的基本表观遗传机制。该提议基于我们最近的发现,即 Avy/a 水坝的后代在子宫内生长受到限制,但会经历产后追赶性生长,并且仅在雌性中表现出成年肥胖。这种体重调节的发育程序差异不是由食物摄入量增加介导的,而是由自发身体活动的持续减弱介导的。我们建议通过实现以下目标来加深对发育不匹配的理解: 目标 1:确定针对身体缺乏活动和肥胖的规划是否需要产后追赶性生长。 Avy/a 小鼠的后代会经历胎儿生长受限,这表明这一过程发生在子宫内。然而,尚不清楚哺乳期的追赶生长是否是“编程”机制的必要组成部分。为了测试这一点,Avy/a 水坝的后代将被培育成正常大小或大窝的 a/a(野生型)水坝,以分别允许或防止哺乳期间的捕获生长。目标 2:确定 Avy/a 小鼠的野生型后代中枢神经系统 DNA 甲基化是否表现出性别特异性、持续性改变。 Avy/a 水坝的雌性野生型后代表现出持续减弱的自发体力活动(笼内活动)和能量消耗。我们将检验以下假设:这些持续变化是由下丘脑和中枢神经系统其他区域 DNA 甲基化的诱导改变介导的。目标 3:检验以下假设:Avy/a 母鼠的膳食甲基供体补充可通过纠正 CNS DNA 甲基化使其雌性后代的体力活动正常化。我们将测试以下假设:在该模型中,促甲基化膳食补充剂通过防止雌性后代下丘脑和其他中枢神经系统区域中异常位点特异性 DNA 低甲基化来使体力活动和肥胖正常化。总体而言,这些研究旨在阐明追赶性生长导致体重调节持续且女性特异性改变的分子机制。了解这些细胞和分子决定因素可能会导致预防和治疗人类肥胖的有效方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ROBERT A WATERLAND其他文献
ROBERT A WATERLAND的其他文献
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{{ truncateString('ROBERT A WATERLAND', 18)}}的其他基金
Systemic interindividual epigenetic variants in African Americans: Identification, characterization, and prospective associations with obesity
非裔美国人的系统性个体间表观遗传变异:鉴定、表征以及与肥胖的前瞻性关联
- 批准号:
10626106 - 财政年份:2021
- 资助金额:
$ 14.26万 - 项目类别:
Systemic interindividual epigenetic variants in African Americans: Identification, characterization, and prospective associations with obesity
非裔美国人的系统性个体间表观遗传变异:鉴定、表征以及与肥胖的前瞻性关联
- 批准号:
10473790 - 财政年份:2021
- 资助金额:
$ 14.26万 - 项目类别:
Systemic interindividual epigenetic variants in African Americans: Identification, characterization, and prospective associations with obesity
非裔美国人的系统性个体间表观遗传变异:鉴定、表征以及与肥胖的前瞻性关联
- 批准号:
10272655 - 财政年份:2021
- 资助金额:
$ 14.26万 - 项目类别:
Unbiased identification and characterization of mouse metastable epialleles
小鼠亚稳态表观等位基因的公正鉴定和表征
- 批准号:
10190936 - 财政年份:2020
- 资助金额:
$ 14.26万 - 项目类别:
Unbiased identification and characterization of mouse metastable epialleles
小鼠亚稳态表观等位基因的公正鉴定和表征
- 批准号:
10032890 - 财政年份:2020
- 资助金额:
$ 14.26万 - 项目类别:
Unbiased identification and characterization of mouse metastable epialleles
小鼠亚稳态表观等位基因的公正鉴定和表征
- 批准号:
10589102 - 财政年份:2020
- 资助金额:
$ 14.26万 - 项目类别:
Unbiased identification and characterization of mouse metastable epialleles
小鼠亚稳态表观等位基因的公正鉴定和表征
- 批准号:
10378095 - 财政年份:2020
- 资助金额:
$ 14.26万 - 项目类别:
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