Epigenetics Embedding of Oral Feeding Skill Development in Preterm Infants

项目摘要/摘要 住进新生儿重症监护病房(NICU)的早产儿承受着多种压力。早期生活 压力可能超过他们的适应能力，并阻碍发展里程碑的实现，如口语 喂食。高达70%的NICU早产儿面临口服喂养的挑战，导致无法茁壮成长 住院，每个婴儿的高额医疗费用高达20万美元。在临床上有相当大的差异。 早产儿口腔喂养技能发展的进展，有些早产儿有更多困难 比其他人更好。有力的证据表明，口腔喂养技能需要完整的神经行为。早期生活 压力会扰乱神经行为的发育，这可能会影响口腔喂养技能的获得。然而， 早期生活压力对口腔喂养技能发展的损害程度及其生物机制 发生的情况是未知的。在神经可塑性敏感期暴露于早期生活应激会导致 应激反应系统的表观遗传印记。早期生活应激导致表观遗传修饰 糖皮质激素相关基因，即NR3C1和HSD11B2的DNA甲基化(DNaM)，它会改变 下丘脑-垂体-肾上腺皮质(HPA)对皮质醇水平和皮质醇反应性的调节 神经行为。早期生活压力造成的表观遗传修饰是持久的，可能会对婴儿的健康产生很大影响 超过新生儿期，增加了终身不适应喂养行为和健康不良的风险。这个 本研究的目的是确定NR3C1和NR3C1dNaM反映的早期生活应激的程度 HSD11B2基因启动子，影响口腔喂养技能的发展。在这项前瞻性纵向研究中， 我们将招募60名临床稳定的早产儿(胎龄28-32周)。我们将评估早期生活 应激、NR3C1和HSD11B2基因启动子的dNaM、皮质醇反应性、神经行为和口服喂养 在NICU住院期间和出院后2周的技能发展。以下是具体目标 地址。目的1.确定早期生活压力、皮质醇反应性和口腔喂养技能之间的关系 发展。目的2.确定NR3C1和HSD11B2的dNaM与皮质醇的关联程度 反应性和/或神经行为。目的3.确定早期生活应激与NR3C1dNaM之间的关系 和HSD11B2，以及口腔喂养技能的发展。拟议的研究将通过以下方式积极影响新生儿护理 贡献了新的知识，澄清了早期生活应激妥协的生物行为机制 口腔喂养技能发展的进展。这些发现对确定可修改的 可以有针对性地促进最佳口腔喂养、更好的营养和更低的终身风险的过程 不适应的饮食行为。

PROJECT SUMMARY/ABSTRACT Preterm infants admitted to the Neonatal Intensive Care Unit (NICU) endure a multitude of stressors. Early life stress may exceed their adaptive capacity and impede achievement of developmental milestones, such as oral feeding. Up to 70% of NICU preterm infants are challenged to feed orally, leading to failure to thrive, prolonged hospitalization, and high healthcare costs up to $200K per infant. There is considerable variation in the clinical progression of oral feeding skill development across preterm infants, with some infants having more difficulty than others. Robust evidence demonstrates that oral feeding skills require intact neurobehaviors. Early life stress disrupts neurobehavior development, which may compromise achievement of oral feeding skills. Yet, the extent to which early life stress impairs oral feeding skill development and the biomechanism whereby this occurs are unknown. Exposure to early life stress during sensitive periods of neuroplasticity results in epigenetic imprinting of stress response systems. Early life stress results in epigenetic modification of glucocorticoid-related genes, i.e., DNA methylation (DNAm) of NR3C1 and HSD11B2, which alters hypothalamic pituitary adrenocortical (HPA) regulation of cortisol levels and cortisol reactivity, disrupting neurobehaviors. Epigenetic modifications due to early life stress are durable and may affect infants’ health far beyond the neonatal period, increasing risk for life-long maladaptive feeding behaviors and poor health. The purpose of this study is to determine the extent to which early life stress, reflected by DNAm of NR3C1 and HSD11B2 gene promoters, compromises oral feeding skill development. In this prospective longitudinal study, we will enroll 60 clinically stable preterm infants (28-32 weeks gestational age). We will evaluate early life stress, DNAm of NR3C1 and HSD11B2 gene promoters, cortisol reactivity, neurobehaviors, and oral feeding skill development during NICU stay and at 2-weeks post-discharge. The following specific aims will be addressed. Aim 1. Determine the association among early life stress, cortisol reactivity, and oral feeding skill development. Aim 2. Determine the extent to which DNAm of NR3C1 and HSD11B2 is associated with cortisol reactivity and/or neurobehaviors. Aim 3. Determine the association among early life stress, DNAm of NR3C1 and HSD11B2, and oral feeding skill development. The proposed study will positively impact neonatal care by contributing novel knowledge that clarifies biobehavioral mechanisms whereby early life stress compromises progression of oral feeding skill development. The findings hold significant promise to identify modifiable processes that can be targeted to promote optimal oral feeding, better nutrition, and lower risk for life-long maladaptive eating behaviors.