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

疼痛/压力对早产儿线粒体功能和神经发育影响的综合组学分析

• 批准号: 10389059
• 负责人: Tingting Zhao
• 金额: $ 4.55万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-06 至 2023-01-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389059
• 关键词: 37 weeks gestation; 5' -AMP-activated protein kinase; Acetylation; Acute; Adult; Affect; Age; Antioxidants; Attention; Behavior Disorders; Biogenesis; Biological; Biological Markers; Cellular Stress; Childhood; Data; Development; Educational workshop; Enrollment; Event; Exercise; Exposure to; Family; Functional disorder; Funding; Future; Gene Expression; Gene Proteins; Genes; Gestational Age; Goals; Grant; Growth and Development function; Heat shock proteins; Homologous Gene; Hospitalization; Human; Impairment; Infant; Infant Care; Infant Development; Intervention; Knowledge; Length of Stay; Life; Liquid Chromatography; Longitudinal prospective study; Measures; Mentorship; Mitochondria; Molecular; National Research Service Awards; Nature; Neonatal; Neonatal Intensive Care; Neonatal Intensive Care Units; Nervous System Trauma; Nervous system structure; Nociceptors; Outcome; PPAR gamma; Pain; Pain Threshold; Parents; Pathway interactions; Pattern; Persistent pain; Phosphorylation; Play; Population; Post-Translational Protein Processing; Pre-Clinical Model; Premature Infant; Procedures; Protein Kinase; Proteins; Proteome; RNA; Reactive Oxygen Species; Regulation; Reporting; Research; Research Project Grants; Sampling; Sex Differences; Sex Differentiation; Spinal cord posterior horn; Stress; Subgroup; Swab; Testing; Time; Training; Vulnerable Populations; Work; daily pain; digital; effective intervention; experience; follow-up; insight; mitochondrial dysfunction; multiple omics; neurobehavior; neurobehavioral; neurodevelopment; pre-clinical; programs; research study; response; secondary analysis; sex; stressor; symposium; tandem mass spectrometry; transcriptome; transmission process

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.

摘要 全世界每年约有1500万婴儿早产（胎龄<37周）。更 在平均新生儿重症监护（NICU）期间， 导致神经发育障碍，这种障碍可能会持续到儿童期甚至成年期。虽然 线粒体功能障碍被发现与疼痛/压力和神经病理学状况有关， 在新生儿群体中的证据，以及婴儿疼痛的性别相关差异的生物学机制， 未知申请人在临床前模型中的初步研究表明，由运动引起的应激诱导 线粒体生物合成主要通过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线粒体自噬。我们假设，疼痛/压力的经验， 早产儿的早期生活将影响线粒体功能/功能障碍， NICU的神经行为结果持续一年以上。拟议的两年培训和研究 研究将使用NICU住院期间和8-12个月时的婴儿数据和样本进行二次分析 一项大型前瞻性纵向研究（NR 016928，PI：Cong）的校正年龄（CA）。申请人将 检查：1）疼痛/应激水平与PGC-1家族、AMPK、 SIRT-1和GCN 5基因与NICU住院和8-12个月CA期间线粒体功能/功能障碍相关; 2)疼痛/应激水平与PGC-1家族磷酸化蛋白水平之间的关系， 在NICU停留期间和8-12个月CA期间的乙酰化和O-GlcNAc化;和3）婴儿性别的关联， 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，功能/功能障碍与神经行为结局。申请人将随机选择25名早产儿 来自父母R 01研究的每个性别亚组的婴儿（N=50）。主要措施包括：每日 NICU住院期间的疼痛/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]）;贝利婴儿发育量表III测试， 12个月CA; PGC-1家族（PGC-1α、PGC-1β和PGC-1相关辅激活因子[PRC]）的基因表达， 36-38周时AMPK、SIRT-1和GCN 5和PGC-1家族磷酸化、乙酰化和O-GlcNAc化 CA和8 - 12个月CA。来自NRSA F31赠款的资金将为赵女士的 论文研究项目，相关课程的注册，培训，讲习班和研讨会，会议 并获得实践和专家指导。