Molecular Basis and Consequences of Early Developmental Epigenetic Programming

早期发育表观遗传编程的分子基础和后果

• 批准号: 8049656
• 负责人: David Serre
• 金额: $ 39.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049656
• 关键词: Adipose tissue; Adult; Affect; Age; American; Animal Model; Animals; Biological; Biological Assay; Body Weight; Body fat; Brain; Complement; DNA Methylation; Development; Diet; Disease; Eating; Embryo; Environment; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Epidemiology; Epigenetic Process; Etiology; Exercise; Expenditure; Fasting; Fat-Restricted Diet; Fatty acid glycerol esters; Female; Fetal Tissues; Fetus; Gene Expression; Gene Expression Profiling; Genes; Genomics; Glucose; Glucose tolerance test; Health; Insulin; Lactation; Life; Liver; Location; Maternal Behavior; Measurement; Measures; Metabolic; Methionine Metabolism Pathway; Methods; Molecular; Molecular Profiling; Mothers; Mus; Muscle; Nature; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Nutritional status; Obesity; Organ; Pancreas; Partner in relationship; Pathway interactions; Pattern; Phenotype; Plasma; Plasma Proteins; Pregnancy; Pregnant Women; Prevalence; Public Health; Risk Factors; Skeletal Muscle; Staging; Stimulus; Stress; Testing; Tissues; Translating; Translations; United States; base; blood glucose regulation; fasting blood glucose level; feeding; genome-wide; juvenile animal; mRNA Expression; mature animal; moderate obesity; mother nutrition; mouse model; novel; offspring; postnatal; programs; pup; response; small molecule; tool; trait

DESCRIPTION (provided by applicant): More than 100 million Americans are obese and 17 million are affected by type 2 diabetes. While diet and lack of physical exercise are the main risk factors for these diseases, several epidemiological and animal studies have shown that the intrauterine nutritional conditions can also influence body weight and glucose homeostasis in adulthood. We hypothesize that maternal nutrition influences the intrauterine environment and can induce genome-wide DNA methylation changes in multiple organs of the fetus. We hypothesize that this epigenetic programming is responsible for translating intrauterine stress into molecular responses that can durably affect the health of the offspring. We propose to test this hypothesis by studying a mouse model of diet-induced maternal obesity using a unique combination of high-throughput genomic tools: the characterization of the genome-wide DNA methylation patterns, using a novel sequencing developed in our lab, and extensive gene expression profiling in multiple tissues. We will study embryos and newborns from C57BL6 dams fed on high- fat or low-fat diet prior and during pregnancy to characterize the molecular basis of intrauterine programming. We will also analyze older animals to understand the lasting molecular and phenotypic consequences of maternal obesity. Our findings will provide a better understanding of the mechanisms responsible for the life-long metabolic consequences of maternal obesity, which currently affects 20-40% of pregnant women in the US. PUBLIC HEALTH RELEVANCE: Maternal obesity currently affects 20-40% of pregnant women in the United States and is a growing public health concern since the offspring of obese mother tend to develop obesity and type 2 diabetes in adulthood. We propose to study the molecular consequences of maternal obesity using a mouse model of diet-induced obesity and state-of-the-art genomic methods. Our findings will provide a better understanding of the biological mechanisms underlying the translation of intrauterine stress into life-long health consequences.

描述(申请人提供)：超过1亿美国人肥胖，1700万人患有2型糖尿病。虽然饮食和缺乏体育锻炼是这些疾病的主要危险因素，但一些流行病学和动物研究表明，宫内营养状况也会影响成年后的体重和血糖动态平衡。我们假设，孕妇的营养会影响宫内环境，并能在胎儿的多个器官中诱导全基因组DNA甲基化变化。我们推测，这种表观遗传程序负责将宫内应激转化为分子反应，从而可持续地影响后代的健康。我们建议通过使用高通量基因组工具的独特组合来研究饮食诱导的母体肥胖的小鼠模型来验证这一假设：使用我们实验室开发的新序列来表征全基因组DNA甲基化模式，以及在多个组织中进行广泛的基因表达谱分析。我们将研究孕前和孕期饲喂高脂或低脂饮食的C57BL6母羊的胚胎和新生儿，以表征宫内编程的分子基础。我们还将分析年长的动物，以了解母体肥胖的持久分子和表型后果。我们的发现将有助于更好地理解导致母体肥胖终生代谢后果的机制，目前美国有20%-40%的孕妇受到肥胖的影响。 与公共卫生相关：在美国，母亲肥胖目前影响着20-40%的孕妇，而且由于肥胖母亲的后代在成年后往往会患上肥胖症和2型糖尿病，这是一个日益严重的公共卫生问题。我们建议使用饮食诱导肥胖的小鼠模型和最先进的基因组方法来研究母体肥胖的分子后果。我们的发现将更好地理解宫内压力转化为终身健康后果的生物学机制。