Molecular Basis of Early Childhood Obesity Programming by Intrauterine Growth Restriction

通过宫内生长受限进行儿童早期肥胖规划的分子基础

• 批准号: 10116433
• 负责人: MAUREEN J CHARRON
• 金额: $ 67.87万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116433
• 关键词: Address; Adipose tissue; Adult; Age-Months; Behavior; Behavioral; Biological; Birth; CD3 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cell physiology; Cells; Cessation of life; Child; Childhood; DNA Methylation; Data; Development; Diabetes Mellitus; Enrollment; Environment; Environmental Risk Factor; Epidemic; Epigenetic Process; Equilibrium; Exposure to; Fetal Growth; Fetal Growth Retardation; Fetus; Gene Expression; Genetic; Genome; Genotype; Gestational Age; Goals; Growth; Health; Hypermethylation; Immune; Infant; Inflammation; Inflammatory; Insulin Resistance; Intervention; Knowledge; Lead; Life; Life Cycle Stages; Link; Low Birth Weight Infant; Measures; Mediating; Metabolic; Metabolic Diseases; Molecular; Monitor; Mononuclear; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acid Regulatory Sequences; Obesity; Pathogenesis; Pathway interactions; Phase; Phenotype; Play; Population; Preventive therapy; Process; Prospective cohort; Regulation; Regulatory T-Lymphocyte; Research Design; Risk; Role; Shapes; Signal Transduction; Statistical Data Interpretation; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Tissue Differentiation; Umbilical Cord Blood; Validation; Variant; Weight Gain; base; cardiovascular disorder risk; cell behavior; cell type; cohort; comorbidity; early childhood; early detection biomarkers; epidemiology study; epigenomics; feeding; fetal; genome wide methylation; high risk; impaired glucose tolerance; insight; insulin sensitivity; interest; male; monocyte; mortality; multilevel analysis; obesity biomarkers; obesity development; obesity in children; obesity risk; overweight child; peripheral blood; postnatal; prenatal exposure; programs; prospective; public health relevance; rapid growth; response; risk stratification; transcription factor

Project Summary Epidemiological studies of multiple cohorts suggest an increased risk for obesity, cardiovascular disease- related death and type 2 diabetes in low birth weight infants. However, the molecular mechanisms underlying developmental programming of childhood obesity remain poorly understood. Alterations in DNA methylation during fetal life have been proposed to be one of the mechanisms that regulate this phenotype. Although association studies, using surrogate cells from cord or peripheral blood, demonstrate a relationship between changes in DNA methylation of loci and infant/child growth parameters, major knowledge gaps exist. Here, we address major questions about early childhood obesity programming by studying purified subpopulations of CD3+ T-cells from intrauterine growth restricted (IUGR) newborns who have an increased risk for obesity and other metabolic disorders in adult life. We elected to study CD3+ T-cells because of their crucial role in the regulation of adipose tissue inflammation and insulin sensitivity, factors which underlie obesity pathogenesis. We hypothesize that the adverse developmental milieu associated with IUGR will be strongly correlated with (1) altered DNA methylation profiles, and (2) functional changes in CD3+ T-cell subpopulations (e.g., CD4+, CD8+, regulatory T-cells ( Tregs)) that persist in peripheral blood T-cells until at least 24-months of age. Furthermore, the enduring epigenetic dysregulation of CD3+ T-cells and their inflammatory signaling processes will be tightly associated with increased adiposity in childhood. We propose three specific aims to address our hypothesis. In Aim 1, we will characterize the effect of IUGR on DNA methylation profiles in purified CD3+ T-cells obtained from cord blood in a prospective cohort of 300 healthy term infants at birth. The persistence of these changes in differentially methylated loci (DML) will be assessed in peripheral blood CD3+ T-cells at 24-months of age. In Aim 2, we will characterize the effect of IUGR-associated DNA methylation on CD3+ T-cell function and gene expression using purified CD4+, CD8+, and Treg cells. In Aim 3, we will determine whether DNA methylation and functional profiles of CD3+ T-cell subpopulations are associated with growth velocity and development of adiposity in the first 24-months of life. Our ultimate goal is to identify epigenetic mechanisms underlying IUGR-mediated childhood obesity in a prospectively enrolled, longitudinally followed cohort of healthy term IUGR infants compared to appropriate for gestational age (AGA) newborns. Furthermore, we will characterize functional changes associated with the newly discovered DML in CD3+ T-cells, a mechanistically relevant cell type in the pathogenesis of obesity.

项目摘要 多个队列的流行病学研究表明，肥胖、心血管疾病的风险增加， 低出生体重儿的相关死亡和2型糖尿病。然而，潜在的分子机制 儿童肥胖的发育程序仍然知之甚少。DNA甲基化的改变 在胎儿生命期间，已被认为是调节这种表型的机制之一。虽然 使用脐带血或外周血的替代细胞进行的相关性研究表明， 基因座DNA甲基化和婴儿/儿童生长参数的变化，存在重大的知识差距。这里我们 通过研究纯化的亚群来解决有关早期儿童肥胖规划的主要问题， 肥胖风险增加的宫内生长受限（IUGR）新生儿的CD 3 + T细胞， 其他代谢紊乱。我们选择研究CD 3 + T细胞，因为它们在免疫系统中起着至关重要的作用。 调节脂肪组织炎症和胰岛素敏感性，这些因素是肥胖发病机制的基础。 我们推测，与IUGR相关的不良发育环境与IUGR的发生密切相关。 具有（1）改变的DNA甲基化谱，和（2）CD 3 + T细胞亚群的功能变化（例如， CD 4+、CD 8+、调节性T细胞（TCRs））持续存在于外周血T细胞中，直至至少24个月， 年龄此外，CD 3 + T细胞及其炎症信号的持久表观遗传失调 这些过程将与儿童时期肥胖症的增加密切相关。我们提出三个具体目标 来验证我们的假设 在目的1中，我们将描述IUGR对获得的纯化的CD 3 + T细胞中DNA甲基化谱的影响。 来自300名出生时健康足月婴儿的前瞻性队列的脐带血。这些变化的持续性 将在24月龄时的外周血CD 3 + T细胞中评估差异甲基化基因座（DML）。 在目标2中，我们将描述IUGR相关DNA甲基化对CD 3 + T细胞功能的影响， 使用纯化的CD 4+、CD 8+和Treg细胞进行基因表达。 在目标3中，我们将确定CD 3 + T细胞亚群的DNA甲基化和功能谱是否与T细胞亚群的DNA甲基化和功能谱相关。 与出生后24个月内的生长速度和肥胖症的发展有关。 我们的最终目标是确定IUGR介导的儿童肥胖的表观遗传机制， 前瞻性入组，纵向随访健康足月IUGR婴儿队列， 胎龄（阿加）新生儿。此外，我们还将描述与此相关的功能变化。 在CD 3 + T细胞中新发现的DML，这是肥胖发病机制中的一种机制相关细胞类型。