Multi-Omics Analysis of Pain/Stress Impact on Neurodevelopment in Preterm Infants

项目摘要 尽管早产儿的存活率有了很大提高，但人们仍然担心， 显著的神经系统发病率和长期的不良后果相关的侮辱对 不成熟的免疫和脑肠道微生物群系统受到痛苦/压力的早期生活的影响 在新生儿重症监护室（NICU）住院期间的经验。我们初步的K23结果显示 累积的疼痛/压力事件与较高的肠道 肠杆菌（门：变形菌），一种典型的生态失调模式，可能 在NICU停留期间导致神经发育缺陷。根据这些结果， 推动这项研究的主要假设是， 早期生活加上肠道生态失调和特定的遗传易感性增加了 早产儿在婴儿期和早期神经发育发病率的风险 童年. 前瞻性纵向设计将用于检查：1）累积的影响 NICU中的疼痛/应激事件以及婴儿肠道微生物组发育的沿着 短期（NICU住院）和长期（随访）的神经发育结局; 2） 宿主遗传学、肠道微生物组和生命早期疼痛/应激事件对婴儿的相互作用 神经发育结果，同时控制性别，喂养和其他环境因素 随着时间的推移的因素;和3）不同程度的疼痛/压力体验对肠道的影响 微生物组和神经发育结果以及使用双胞胎的其他生长参数， 对.拟议的4年项目将招募和跟踪200名早产儿（160名婴儿在 NICU住院期间直至18-24个月的最终分析（考虑损耗） 校正年龄（CA）。NICU中的主要测量包括每日疼痛/应激事件（NICU 婴儿压力源量表）、肠道微生物组模式和功能（粪便样本：每周两次; 16 S rRNA基因和宏基因组测序）、宿主遗传学（全外显子组测序以鉴定 影响神经肠道免疫信号传导的遗传变异）、自主反应（每周;心脏 心率变异性）和神经发育结局（36周CA; NICU网络 神经行为量表）。在随访中，肠道微生物组，神经发育结果， 包括疼痛敏感性将在CA 4、8-12和18-24个月时测量。

PROJECT SUMMARY Despite substantial gains in survival of preterm infants, concerns remain regarding the significant neurological morbidity and long-term adverse outcomes related to insults on the immature immune and brain-gut-microbiota systems affected by painful/stressful early life experience during the neonatal intensive care (NICU) stay. Our preliminary K23 results show that cumulative pain/stress events are significantly associated with higher abundance of gut Enterobacteria (Phylum: Proteobacteria), a characteristic pattern of dysbiosis, which may contribute to neurodevelopmental deficits during the NICU stay. In light of these results, the primary hypothesis driving this research is that cumulative pain/stress experienced in early life combined with gut dysbiosis and specific genetic susceptibilities increase the risk of neurodevelopmental morbidity in preterm infants during infancy and early childhood. A prospective longitudinal design will be used to examine: 1) the impact of cumulative pain/stress events in the NICU along with gut microbiome development on infant neurodevelopmental outcomes over the short- (NICU stay) and long-term (follow-up); 2) interaction effects of host genetics, gut microbiome, and early life pain/stress events on infant neurodevelopmental outcomes, while controlling for sex, feeding and other environmental factors over time; and 3) the impact of different levels of pain/stress experiences on the gut microbiome and neurodevelopment outcomes as well as other growth parameters using twin- pairs. The proposed 4-year project will recruit and follow 200 preterm infants (160 infants in the final analysis considering the attrition) during NICU hospitalization and until 18-24 months corrected age (CA). Primary measures in the NICU include daily pain/stress events (NICU Infant Stressor Scale), gut microbiome patterns and function (stool sample: twice/week; 16S rRNA gene and metagenomic sequencing), host genetics (whole exome sequencing to identify genetic variants that effect neuro-gut-immune signaling), autonomic responses (weekly; heart rate variability) and neurodevelopmental outcomes (at 36 weeks CA; NICU Network Neurobehavioral Scale). At follow-up visits, gut microbiome, neurodevelopmental outcomes, including pain sensitivity will be measured at 4, 8-12, and 18-24 months CA.