Epigenetics Embedding of Oral Feeding Skill Development in Preterm Infants

项目总结/摘要 进入新生儿重症监护室（NICU）的早产儿承受着多种压力。早期生活 压力可能会超过他们的适应能力，并阻碍实现发展里程碑，如口腔 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， 住院治疗，以及每个婴儿高达20万美元的高额医疗费用。在临床上有相当大的差异， 早产儿经口喂养技能发展的进展，一些婴儿有更多的困难 than others.强有力的证据表明，口服喂养技能需要完整的神经行为。早期生活 压力会破坏神经行为的发展，这可能会影响到口服喂养技能的实现。然而， 早期生活压力损害口服喂养技能发展的程度和生物机制， 发生是未知的。在神经可塑性的敏感时期暴露于早期生活压力会导致 压力反应系统的表观遗传印记。早期生活压力导致表观遗传修饰 糖皮质激素相关基因，即，NR 3C 1和HSD 11B 2的DNA甲基化（DNAm）， 下丘脑垂体肾上腺皮质（HPA）调节皮质醇水平和皮质醇反应性，破坏 神经行为由于早期生活压力引起的表观遗传修饰是持久的，可能会影响婴儿的健康， 超过新生儿期，增加终身不适应喂养行为和健康状况不佳的风险。的 本研究的目的是确定NR 3C 1和NR 3C 1DNAm反映的早期生活压力的程度， HSD 11B 2基因启动子，影响经口进食技能的发展。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、NR 3C 1和HSD 11B 2基因启动子DNAm、皮质醇反应性、神经行为和经口摄食 NICU住院期间和出院后2周的技能发展。以下具体目标将是 处理。目标1。确定早期生活压力、皮质醇反应性和口饲技能之间的关系 发展目标二。确定NR 3C 1和HSD 11B 2的DNAm与皮质醇相关的程度 反应性和/或神经行为。目标3。确定早期生活应激与NR 3C 1的DNAm之间的关系 和HSD 11B 2，以及口服喂养技能的发展。拟议的研究将对新生儿护理产生积极影响， 贡献新的知识，澄清生物行为机制，使早期生活压力损害 口腔喂养技能的发展。这些发现对识别可修改的 可以有针对性地促进最佳口服喂养，更好的营养和降低终身风险的过程 不良饮食行为

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.