Epigenetic programming of infant mesenchymal stem cells: mechanisms for obesity and diabetes risk in humans

婴儿间充质干细胞的表观遗传编程：人类肥胖和糖尿病风险的机制

基本信息

批准号：
10441451
负责人：
Kristen Elizabeth Boyle
金额：
$ 29.95万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-25 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10441451
关键词：
5&apos -AMP-activated protein kinase Address Animal Model Animals Basic Science Biological Assay Birth Body mass index Cellular Metabolic Process Child Citric Acid Cycle Clinical DNA DNA Methylation Data Development Diabetes Mellitus Electron Transport Energy Metabolism Enzymes Epigenetic Process Exhibits Fasting Fatty Acids Fatty acid glycerol esters Genes Genetic Glucose Goals Health Human Hyperinsulinism Hypermethylation Impairment In Vitro Infant Insulin Insulin Resistance Investigation Knowledge Lead Life Lipids Maternal Exposure Measures Mesenchymal Stem Cells Metabolic Metabolic stress Metabolism Methylation Mitochondria Modeling Molecular Mothers Nutrient Obesity Outcome Overweight Pathway interactions Phenotype Physical activity Play Population Sciences Prevention Prevention strategy Protein Kinase Publishing Regulation Reporter Resources Risk Role Sampling Skeletal Muscle Stimulus Succinate Dehydrogenase System Testing Tissues Umbilical Cord Blood Umbilical cord structure Weight Woman clinically relevant cohort diabetes risk fatty acid oxidation fetal in utero infant adiposity infant outcome knock-down lifestyle factors lipid metabolism maternal obesity metabolic phenotype mitochondrial dysfunction myogenesis neonatal outcome novel novel therapeutic intervention nutrition obese mothers obesity in pregnancy obesity prevention obesity risk offspring offspring obesity overexpression oxidation prepregnancy response stem cell model translational approach

项目摘要

PROJECT SUMMARY/ABSTRACT Children born to mothers with obesity are at increased risk for developing obesity and diabetes later in life, independent of lifestyle factors, such as physical activity or nutrition. While some children born to obese mothers will not go on to develop obesity or insulin resistance, for those who do, little is known about how maternal exposures (e.g., hyperinsulinemia) may influence child outcomes in humans. We use human, infant mesenchymal stem cells (MSCs), cultured from umbilical cord tissue collected at birth, for investigating mechanisms of obesity and diabetes risk in humans. Human and animal studies, as well as our own MSC data, show strong association between maternal, MSC and infant metabolism. For example, MSCs from infants born to obese vs. normal weight mothers have perturbations in lipid metabolism and energy sensing molecules regulating lipid metabolism, such as AMP-activated protein kinase (AMPK), which we observed at the epigenetic level (DNA methylation). Ob-MSCs also have impaired AMPK activation in response to metabolic stress in vitro, which could compromise lipid partitioning and shifts in fuel utilization in response to metabolic stimuli. Moreover, MSC lipid metabolism correlates with fat mass of the infants measured at birth. These observations make this a novel model in which to investigate the epigenetic programming of human metabolic phenotypes in vitro. Our unique, translational approach allows us to maintain human variability in a basic science model. Such integration of mechanistic investigation with clinical samples will help us to achieve our long-term goal of understanding mechanisms for the developmental programming of metabolism at the molecular level in humans. This project will not only advance the field for understanding the molecular underpinnings of human developmental programming, but may also identify modifiable maternal factors contributing to offspring phenotype supporting implementation of critically needed obesity prevention strategies. Therefore, the central hypothesis for this proposal is that perturbations in maternal metabolism induce infant MSC epigenetic signatures promoting dysregulation of cellular fuel switching and mitochondrial dysfunction. This project leverages our unique resource of MSCs already collected from >150 infants as part of a well characterized, longitudinal pre-birth cohort (Healthy Start, R01DK076648). Thus, while Aims 1&2 will determine mechanisms for altered lipid partitioning and mitochondrial dysfunction in MSCs from infants born to normal weight versus obese mothers, Aim 3 will expand this knowledge to population science, validating our preliminary data in a larger cohort. Aim 1 will determine the impact of maternal obesity-induced epigenetic signatures on offspring MSC fuel switching and lipid partitioning in response to changes in nutrient supply. Aim 2 will determine whether epigenetic signature promotes mitochondrial dysfunction and reduced substrate oxidation in Ob- vs. NW-MSCs. Aim 3 will substantiate the clinical relevance of the umbilical cord MSC model using specific tests to determine maternal metabolic measures predictive of MSC metabolism and, in turn, MSC metabolic measures predictive of infant outcomes.

项目概要/摘要肥胖母亲所生的孩子在以后的生活中患肥胖症和糖尿病的风险会增加，独立于生活方式因素，例如体力活动或营养。虽然有些孩子是肥胖母亲生下的不会继续发展为肥胖或胰岛素抵抗，对于那些发展为肥胖或胰岛素抵抗的人，我们对母亲如何暴露（例如高胰岛素血症）可能会影响人类的儿童结局。我们使用人类、婴儿间充质干细胞 (MSC)，从出生时收集的脐带组织中培养，用于研究人类肥胖和糖尿病风险的机制。人类和动物研究，以及我们自己的 MSC 数据，显示母体、间充质干细胞和婴儿代谢之间存在很强的相关性。例如，来自出生婴儿的间充质干细胞肥胖与正常体重母亲的脂质代谢和能量传感分子存在干扰调节脂质代谢，例如我们在表观遗传学中观察到的 AMP 激活蛋白激酶 (AMPK) 水平（DNA 甲基化）。 Ob-MSCs 在体外响应代谢应激时 AMPK 激活也受损，这可能会损害脂质分配和燃料利用率因代谢刺激而发生的变化。而且， MSC 脂质代谢与出生时测量的婴儿脂肪量相关。这些观察使这体外研究人类代谢表型的表观遗传编程的新模型。我们的独特的转化方法使我们能够在基础科学模型中保持人类的变异性。这样的整合利用临床样本进行机制研究将有助于我们实现理解的长期目标人类分子水平上代谢发育编程的机制。这个项目不仅将推进理解人类发育分子基础的领域编程，但也可能确定有助于后代表型支持的可改变的母体因素实施急需的肥胖预防战略。因此，这个问题的中心假设提议认为，母体代谢的扰动会诱导婴儿 MSC 表观遗传特征，从而促进细胞燃料转换失调和线粒体功能障碍。该项目利用了我们独特的资源的 MSC 已从超过 150 名婴儿中收集，作为特征明确的纵向出生前队列的一部分（健康开始，R01DK076648）。因此，虽然目标 1 和 2 将确定改变脂质分配和正常体重婴儿与肥胖母亲所生婴儿间充质干细胞线粒体功能障碍，目标 3 将扩大这些知识应用于人口科学，在更大的队列中验证我们的初步数据。目标 1 将确定母体肥胖诱导的表观遗传特征对后代 MSC 燃料转换和脂质分配的影响以应对养分供给的变化。目标 2 将确定表观遗传特征是否促进 Ob- 与 NW-MSC 相比，线粒体功能障碍和底物氧化减少。目标 3 将证实使用特定测试确定母体代谢的脐带间充质干细胞模型的临床相关性 MSC 代谢的预测指标，反过来，MSC 代谢指标也可预测婴儿的结局。