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

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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.