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

• 批准号: 10197911
• 负责人: Kristen Elizabeth Boyle
• 金额: $ 32.1万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-25 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197911
• 关键词: 5' -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; Pregnancy; 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 prevention; obesity risk; offspring; offspring obesity; overexpression; oxidation; prepregnancy; response; stem cell model; translational approach

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.

项目摘要/摘要 肥胖母亲所生的孩子有增加肥胖症和糖尿病后期的风险， 独立于生活方式因素，例如体育锻炼或营养。肥胖母亲出生的一些孩子 不会继续发展肥胖或胰岛素抵抗，因为那些这样做的人几乎不知道母亲 暴露（例如高胰岛素血症）可能会影响人类的儿童结果。我们使用人类，婴儿 从出生时收集的脐带组织培养的间充质干细胞（MSC）用于研究 肥胖和糖尿病的机制在人类中风险。人类和动物研究以及我们自己的MSC数据 表现出孕产妇，MSC和婴儿代谢之间的密切关联。例如，来自婴儿出生的硕士学位 肥胖与正常体重母亲在脂质代谢和能量传感分子中具有扰动 调节脂质代谢，例如AMP激活的蛋白激酶（AMPK），我们在表观遗传学上观察到了这一点 水平（DNA甲基化）。 OB-MSC还响应体外代谢应激而受损AMPK激活， 这可能会损害脂质分配和燃料利用的转移，以响应代谢刺激。而且， MSC脂质代谢与出生时测量的婴儿的脂肪质量相关。这些观察结果使得 在体外研究人代谢表型的表观遗传编程的新型模型。我们的 独特的转化方法使我们能够在基本科学模型中保持人类可变性。这样的整合 通过临床样本进行的机械调查将有助于我们实现我们的长期理解目标 人类分子水平上新陈代谢发展的机制。这个项目 不仅将进步了解人类发育的分子基础 编程，但也可以识别可修改的母亲因素，从而有助于后代表型支持 实施急需的肥胖预防策略。因此，为此的中心假设 建议是孕产妇代谢的扰动诱导婴儿MSC表观遗传学特征促进 细胞燃料开关和线粒体功能障碍的失调。该项目利用我们的独特资源 在> 150个婴儿中已经收集的MSC，这是一个表征良好的纵向前生前队列的一部分（健康 开始，R01DK076648）。因此，尽管目标1和2将确定改变脂质分区的机制，并且 来自出生的婴儿到正常体重与肥胖母亲的MSC的线粒体功能障碍，AIM 3将扩展 这对人群科学的知识，验证了我们在更大的队列中的初步数据。 AIM 1将确定 孕产妇肥胖引起的表观遗传学特征对后代MSC燃料开关和脂质分配的影响 响应营养供应的变化。 AIM 2将确定表观遗传签名是否促进 线粒体功能障碍和OB-NW-MSC中的底物氧化减少。 AIM 3将证实 使用特定测试确定母体代谢的脐带MSC模型的临床相关性 衡量MSC代谢的预测，进而预测MSC代谢量度的预测婴儿预后。