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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：
ROBERT A WATERLAND
金额：
$ 14.26万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
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

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.