Integrative omics analysis of pain/stress impact on mitochondrial function and neurodevelopment in preterm infants

摘要 每年，全球约有1500万名婴儿早产(胎龄37周)。更多 在他们平均入住新生儿重症监护病房(NICU)期间，可能会有300多个必要但有侵入性的手术 导致神经发育障碍，这种损害可能会持续到他们的童年甚至成年。虽然 线粒体功能障碍与疼痛/应激和神经病理状况有关，缺乏 在新生儿人群中的证据，性别相关婴儿疼痛差异的生物学机制是 未知。申请人在临床前模型中的初步研究表明，运动引起的压力会导致 线粒体生物发生主要通过PGC-1a/Akt途径和过度暴露于活性氧 (ROS)导致线粒体功能障碍和有丝分裂。我们假设疼痛/压力体验在 早产儿的早期生活将影响线粒体功能/功能障碍，从而影响 NICU的神经行为结果持续一年以上。拟议的为期两年的培训和研究 这项研究将使用NICU期间和8-12个月的婴儿数据和样本进行二次分析 来自大型前瞻性纵向研究(NR016928，PI：CONG)的校正年龄(CA)。申请者将会 观察：1)疼痛/应激水平与PGC-1家族、AMPK、 NICU住院期间和CA 8~12个月与线粒体功能/功能障碍相关的Sirt-1和GCN5基因； 2)疼痛/应激水平与PGC-1家族磷酸化蛋白水平的关系； NICU住院期间和8-12个月CA期间的乙酰化和O-GlcN酰化；3)婴儿性别、 疼痛/应激水平、线粒体相关转录组和蛋白质组的表达水平 随着时间的推移，神经行为结果与功能/功能障碍有关。申请者将随机选择25个早产儿 来自父母R01研究的每个性别亚组的婴儿(N=50)。主要措施包括：每天 NICU期间的疼痛/应激事件(NICU婴儿应激源量表[NISS])；神经行为结局(NICU 网络神经行为量表[NNNS])在36-38周CA；贝利婴儿发育量表III测试在8-38周 12个月CA；PGC-1家族基因表达(PGC-1α、PGC-1β和PGC-1相关辅活化子[PRC])， 36-38周AMPK、SIRT-1、GCN5和PGC-1家族的磷酸化、乙酰化和O-GlcN酰化 CA和8-12个月CA。来自NRSA F31基金的资金将为赵女士的 论文研究项目、参加相关课程、培训、工作坊、研讨会、会议 并获得实践经验和专家指导。

Abstract Each year, approximately 15 million infants are born prematurely (<37 weeks gestational age) worldwide. More than 300 necessary but invasive procedures during their average neonatal intensive care (NICU) stay may induce neurodevelopment impairments that may persist in their childhood and even adulthood. Although mitochondrial dysfunction was found associate with pain/stress and neuropathological conditions, there lacks evidence in neonatal population, and the biological mechanisms of sex-related differences in infants’ pain is unknown. The applicant’s preliminary study in preclinical models showed that stress caused by exercise induce mitochondrial biogenesis majorly through PGC-1a/Akt pathway and over-exposure to reactive oxygen species (ROS) causes mitochondrial dysfunction and mitophagy. We hypothesis that pain/stress experience during preterm infants’ early life will affect mitochondrial function/dysfunction and therefore influence the neurobehavioral outcomes from NICU stay over one year of life. The proposed 2-year training and research study will conduct a secondary analysis using infant data and samples during NICU stay and at 8-12 months corrected age (CA) from a large prospective longitudinal study (NR016928, PI: Cong). The applicant will examine: 1) the relationships between levels of pain/stress and expression levels of PGC-1 family, AMPK, SIRT-1 and GCN5 genes related to mitochondrial function/dysfunction during NICU stay and 8-12 months CA; 2) the relationships between levels of pain/stress and protein levels of PGC-1 family phosphorylation, acetylation and O-GlcNAcylation during NICU stay and 8-12 months CA; and 3) the associations of infant sex, levels of pain/stress, expression levels of transcriptome and proteome related to mitochondrial function/dysfunction with neurobehavioral outcomes over time. The applicant will randomly select 25 preterm infants from each sex subgroup from the parents R01 study (N=50). Primary measures include: daily pain/stress events (NICU Infant Stressor Scale [NISS]) during NICU stay; neurobehavioral outcomes (NICU Network Neurobehavioral Scale [NNNS]) at 36-38 weeks CA; Bayley Scale of Infant Development III test at 8- 12 months CA; gene expression of PGC-1 family (PGC-1α, PGC-1β and PGC-1-related coactivator [PRC]), AMPK, SIRT-1 and GCN5 and PGC-1 family phosphorylation, acetylation and O-GlcNAcylation at 36-38 weeks CA and 8 -12 months CA. Funding from this NRSA F31 grant will provide the support for Ms. Zhao’s dissertation research project, enrollment in relevant courses, training, workshops, and seminars, conferences and obtaining hands-on practice and expert mentorship.