Molecular Basis and Consequences of Early Developmental Epigenetic Programming

描述（由申请人提供）：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葡萄糖稳态。我们假设母体营养影响宫内环境，并可诱导胎儿多个器官的全基因组DNA甲基化变化。我们假设这种表观遗传程序负责将宫内应激转化为能够持久影响后代健康的分子反应。为了验证这一假设，我们建议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小鼠模型：基因组DNA甲基化模式的表征，使用我们实验室开发的新测序，以及多种组织中广泛的基因表达谱。我们将研究在怀孕前和怀孕期间饲喂高脂或低脂饮食的C57BL6胚胎和新生儿，以表征宫内编程的分子基础。我们还将分析老年动物，以了解母体肥胖的持久分子和表型后果。我们的研究结果将更好地理解孕产妇肥胖导致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。

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.