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(由申请方提供):发育关键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“发育规划”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是基本的。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,随后是出生后追赶生长):无活力的黄(Avy)小鼠。我们将使用这个模型来研究中枢神经系统(CNS)中介导能量平衡的发育编程的基本表观遗传机制。这一建议建立在我们最近发现的基础上,即Avy/a母鼠的后代在子宫内生长受限,但在出生后追赶生长,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性差异不是通过增加食物摄入来介导的,而是通过自发性身体活动的持续钝化来介导的。我们建议通过实现以下目标来推进我们对发育不匹配的理解:目标1:确定是否需要产后追赶生长来进行身体活动不足和肥胖的编程。Avy/a小鼠的后代经历胎儿生长受限,这表明在子宫内发生的过程。然而,尚不清楚在哺乳期的追赶式增长是否是“方案拟订”机制的必要组成部分。为了测试这一点,将Avy/a母鼠的后代以正常大小或大窝数饲养到a/a(野生型)母鼠中,以分别允许或防止哺乳期的捕获生长。目的2:确定Avy/a小鼠的野生型后代是否表现出CNS中DNA甲基化的性别特异性持续改变。Avy/a母鼠的雌性野生型后代表现出持续迟钝的自发体力活动(笼内活动)和能量消耗。我们将测试的假设,这些持续的变化是介导的诱导下丘脑和其他区域的中枢神经系统的DNA甲基化的改变。目标3:检验以下假设:Avy/a母鼠的膳食甲基供体补充剂通过纠正CNS DNA甲基化使其雌性后代的体力活动正常化。我们将检验这一假设,即前甲基化膳食补充剂通过防止雌性后代下丘脑和其他CNS区域的异常基因座特异性DNA低甲基化,使该模型中的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和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有效的方法来预防和治疗人类肥胖。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ROBERT A WATERLAND其他文献
ROBERT A WATERLAND的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 14.26万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 14.26万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 14.26万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 14.26万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 14.26万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 14.26万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 14.26万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 14.26万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 14.26万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 14.26万 - 项目类别:
Research Grant