Impact of COVID-19 and Structural Racism on Maternal Mental Health and the Bronx MomBa Cohort

项目概要 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 低出生体重婴儿的相关死亡和 2 型糖尿病。然而，其背后的分子机制 对儿童肥胖的发育规划仍知之甚少。 DNA甲基化的改变 胎儿生命期间的这种变化被认为是调节这种表型的机制之一。虽然 关联研究使用来自脐带或外周血的替代细胞，证明了之间的关系 基因座 DNA 甲基化和婴儿/儿童生长参数的变化，存在重大知识差距。在这里，我们 通过研究纯化的儿童肥胖亚群来解决有关早期儿童肥胖规划的主要问题 来自宫内生长受限 (IUGR) 新生儿的 CD3 T 细胞，这些新生儿肥胖和肥胖的风险增加 成人生活中的其他代谢紊乱。我们选择研究 CD3 T 细胞，因为它们在 脂肪组织炎症和胰岛素敏感性的调节，这些因素是肥胖发病机制的基础。 我们假设与 IUGR 相关的不良发育环境密切相关 (1) DNA 甲基化谱改变，以及 (2) CD3 T 细胞亚群的功能变化（例如， CD4、CD8、调节性 T 细胞 (Treg)）在外周血 T 细胞中持续存在至少 24 个月 年龄。此外，CD3 T 细胞及其炎症信号传导的持久表观遗传失调 这些过程与儿童时期肥胖的增加密切相关。我们提出三个具体目标 来解决我们的假设。 在目标 1 中，我们将表征 IUGR 对获得的纯化 CD3 T 细胞中 DNA 甲基化谱的影响 来自 300 名健康足月婴儿的前瞻性队列的脐带血。这些变化的持续性 差异甲基化位点 (DML) 将在 24 月龄时在外周血 CD3 T 细胞中进行评估。 在目标 2 中，我们将描述 IUGR 相关 DNA 甲基化对 CD3 T 细胞功能的影响，以及 使用纯化的 CD4 、CD8 和 Treg 细胞进行基因表达。 在目标 3 中，我们将确定 CD3 T 细胞亚群的 DNA 甲基化和功能谱是否与 与生命前 24 个月内的生长速度和肥胖的发展有关。 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、纵向随访的健康足月 IUGR 婴儿队列与适当的 胎龄（AGA）新生儿。此外，我们将描述与相关的功能变化 CD3 T 细胞中新发现的 DML，CD3 T 细胞是肥胖发病机制中与机制相关的细胞类型。

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.