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Downstream mRNA Target Analysis in Neonatal Hypoxic-Ischaemic Encephalopathy Identifies Novel Marker of Severe Injury: a Proof of Concept Paper

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Abstract

Human microRNA miR-374a is downregulated in the umbilical cord blood (UCB) of infants with hypoxic-ischaemic encephalopathy (HIE). The downstream targets of this microRNA (miRNA) are unclear, but one putative target is the activin-A receptor type IIb (ACVR2B). ACVR2B is required for activin-A function and previous reports have shown alterations of activin-A levels in neonatal HIE. Our aim was to investigate the expression of the potential downstream targets of miR-374a, activin-A and ACVR2B, at birth in a cohort of full-term infants with perinatal asphyxia (PA) only, and those with PA who developed clinical and electrographic HIE. UCB was drawn and processed immediately after delivery. Levels of serum activin-A were measured using ELISA. mRNA levels of ACVR2B in whole blood were quantified using qRT-PCR. Outcome was assessed at 3 years of age using standardised developmental assessment. In total, 171 infants were enrolled: 88 healthy controls, 56 PA and 27 HIE. A statistically significant elevation of median (IQR) ACVR2B was detected in infants with severe HIE compared to moderate/mild HIE, PA and control groups (3.3 (2.94–3.67) vs. 0.91 (0.55–1.21) vs. 0.88 (0.57–1.38) vs. 0.84 (0.74–1.24), p values = 0.04, 0.027 and 0.025, respectively). Although serum activin-A levels were elevated in infants with severe HIE, this elevation did not reach significance. ACVR2B may be a potential novel marker of HIE severity. This is the first study to examine the relationship between activin-A, its receptor AVCR2B and potentially upstream miRNA miR-374a in a cohort of carefully categorised and phenotyped infants. We have shown that miRNA analysis, combined with downstream target exploration, may yield novel biomarkers for the prediction of HIE severity.

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Authors and Affiliations

  1. Neonatal Brain Research Group, Irish Centre for Fetal and Neonatal Translational Research, Department of Paediatrics and Child Health, Cork University Maternity Hospital, Wilton, Cork, Ireland

    A. M. Looney, C. E. Ahearne, G. B. Boylan & D. M. Murray

  2. Neonatal Department, Karolinska Institutet and University Hospital, Stockholm, Sweden

    B. Hallberg

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  1. A. M. Looney
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  2. C. E. Ahearne
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  3. B. Hallberg
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  4. G. B. Boylan
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  5. D. M. Murray
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Correspondence to A. M. Looney.

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Looney, A.M., Ahearne, C.E., Hallberg, B. et al. Downstream mRNA Target Analysis in Neonatal Hypoxic-Ischaemic Encephalopathy Identifies Novel Marker of Severe Injury: a Proof of Concept Paper. Mol Neurobiol 54, 8420–8428 (2017). https://doi.org/10.1007/s12035-016-0330-4

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