Epigenetic Mechanisms in Developmental Mismatch

发育不匹配的表观遗传机制

• 批准号: 9135636
• 负责人: ROBERT A WATERLAND
• 金额: $ 14.26万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9135636
• 关键词: Acceleration; Address; Adult; Adverse effects; Affect; Animal Model; Bioinformatics; Biological; Biology; Birth; Birth Weight; Body Weight; Brain region; Control Groups; DNA; DNA Methylation; Data; Databases; Developed Countries; Development; Diet; Dietary Supplementation; Eating; Energy Metabolism; Environmental Exposure; Epidemic; Epigenetic Process; Exercise; Exhibits; Famines; Female; Fetal Growth Retardation; Fostering; Growth; Health; Home environment; Human; Hypothalamic structure; Individual; Infant; Intervention; Knowledge; Lead; Mediating; Methylation; Modeling; Molecular; Mus; Neuraxis; Neurons; Neurosciences; Nutritional; Obesity; Perinatal; Physical activity; Population; Population Heterogeneity; Predisposition; Pregnancy; Prevention; Process; Regulation; Research; Research Personnel; Risk; Supplementation; Testing; Time; Tissue Banks; Weaning; Woman; critical period; design; developmental nutrition; dietary supplements; effective intervention; energy balance; epidemiologic data; experience; improved; in utero; male; novel; nutrition; offspring; postnatal; prevent; programs; sex

 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（由适用提供）：在关键发展期间的营养影响会导致能源平衡调节的永久变化。迫切需要确定体重调节的这种“发育编程”的程度加剧了全球肥胖的流行，但是我们对基本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展不匹配模型（即胎儿生长限制，然后是产后追赶生长）：Agouti可行的黄色（AVY）小鼠。我们将使用该模型来研究中枢神经系统（CNS）的基本表观遗传机制，该机制中位数能量平衡。这项提案是基于我们最近发现的，即阿维/A大坝的后代在子宫内受到限制，但会发生产后追赶增长，并且仅在女性中暴露了成年肥胖。这种编程的体重调节差异不是通过增加的食物摄入量而是通过持续的赞助体育锻炼来介导的。我们建议通过实现以下目的来提高对发展不匹配的理解：目标1：确定在身体上不活动和肥胖的编程是否需要产后追赶增长。 Avy/A小鼠的后代经历胎儿生长限制，指出子宫内发生的过程。但是，尚不清楚哺乳期间的追赶增长是否是“编程”机制的必需组成部分。为了进行测试，Avy/A大坝的后代将被培育至正常尺寸或大垃圾的A/A（野生型）大坝，以分别允许或防止哺乳期的捕获增长。 AIM 2：确定AVY/A小鼠的野生型后代是否暴露了性别特异性的，在中枢神经系统中DNA甲基化的持续改变。女性野生型后代/大坝暴露于持续钝性的赞助体育活动（家庭笼活动）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其他中枢神经系统的其他区域中DNA甲基化诱导的改变介导的。目标3：检验以下假设：饮食中的甲基供体补充AVY/A大坝通过校正CNS DNA甲基化来使其女性后代的体育活动归一化。我们将通过防止在女性后代中下丘脑和其他中枢神经系统区域中的异常基因座特异性DNA低甲基化来检验，即在该模型中，促甲基化饮食补充剂在该模型中使体育活动和肥胖归一化。总体而言，这些研究旨在阐明追赶生长导致体重调节持续和特定于女性的变化的分子机制。了解这些细胞和分子决定剂可能会导致有效的方法来预防和治疗人类肥胖。