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

项目摘要 对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 儿童肥胖症的发育规划仍然知之甚少。DNA甲基化的改变 在胎儿时期被认为是调节这一表型的机制之一。虽然 使用脐带血或外周血中的替代细胞进行的关联性研究表明， 在基因座DNA甲基化和婴儿/儿童生长参数的变化方面，存在主要的知识差距。在这里，我们 通过研究纯化的亚群来解决有关儿童早期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，这些新生儿肥胖风险增加， 成人生活中的其他代谢紊乱。我们之所以选择研究CD3 T细胞，是因为它们在 脂肪组织炎症和胰岛素敏感性的调节，是肥胖发病的基础因素。 我们假设与胎儿宫内发育迟缓相关的不良发育环境 随着(1)DNA甲基化特征的改变，以及(2)CD3T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，CD3T细胞的持久表观遗传失调及其炎症信号 这一过程与童年时期肥胖症的增加密切相关。我们提出了三个具体目标 来解释我们的假设。 在目标1中，我们将表征IUGR对纯化的CD3T细胞DNA甲基化的影响 在300名出生时健康足月婴儿的前瞻性队列中采集脐带血。这些变化的持久性 在差异方面，将在24个月龄时评估外周血CD3T细胞中的甲基化基因(DML)。 在目标2中，我们将表征IUGR相关DNA甲基化对CD3T细胞功能和 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CD3T细胞亚群的DNA甲基化和功能谱是否 与出生前24个月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学机制。 前瞻性登记，纵向跟踪队列的健康足月IUGR婴儿与合适的 胎龄(AGA)新生儿。此外，我们还将描述与 最近在CD3T细胞中发现了DML，这是一种与肥胖发病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.