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（由申请人提供）：发育关键时期的营养影响会引起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。我们对潜在生物学的了解仍然处于初级阶段，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，随后出生后追赶性生长）：我们将采用刺豚鼠活黄色（Avy）小鼠。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。这种体重调节的发育程序差异不是由食物摄入量增加而是由自发身体活动的持续减弱所介导的，我们建议通过实现以下目标来加深对发育不匹配的理解： 1：确定 Avy/a 小鼠的后代是否需要进行出生后追赶性生长，这表明在子宫内发生的过程是否需要追赶性生长。哺乳期是“编程”机制的一个必要组成部分，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量产仔的 a/a（野生型）水坝，以允许或防止捕获生长。目标 2：确定 Avy/a 小鼠的野生型后代是否表现出性别特异性、中枢神经系统 DNA 甲基化的持续改变。我们将检验这些持续变化是由下丘脑和中枢神经系统其他区域的 DNA 甲基化诱导改变介导的假设。 Avy/a 母鼠的甲基供体补充通过纠正中枢神经系统 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，即在该模型中，促甲基化膳食补充剂通过防止异常基因座特异性 DNA 低甲基化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持续且女性特有的体重变化的分子机制。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。