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-1a, PGC-1ß 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.