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UNICORN study: Underlying mechanisms in Neonatal Immune metaboliC dysregulatiOn and bRain Injury (2016-9)

PI: E Molloy

Collaborators: Prof. Adrienne Foran, Dr. Annie Curtis, Dr. Deirdre Sweetman, Dr. Deirdre Murray, Dr. Ellen Crushell, Prof Ger Boylan, Prof Jim Meaney, Ms Mandy Daly, Prof Richard Porter, Prof Terrie Inder, Dr. Veronica Donoghue

PhD Student: Dr. Mary O'Dea

Institutions: CWIUH, NMh, Rotunda, TCD, RCSI

Background: Neonatal brain injury has a multifactorial aetiology and causes significant neurological morbidity such as cerebral palsy. Therapeutic hypothermia (TH) is the only treatment available for neonatal encephalopathy (NE) but morbidity and mortality rates remain high. There is an urgent need for adjunctive therapies to improve neurodevelopmental outcomes. Persistent inflammation: Persistent systemic inflammation has been implicated in neonatal brain injury and identifying new inflammatory biomarkers will help to determine the aetiology of NE and new adjunctive therapies. There is a narrow therapeutic window to activate neuroprotective therapies during ischaemic reperfusion in NE. Ischaemia reperfusion injury occurs when a hypoxic tissue is reperfused rapidly in NE resulting in oxidative damage, cellular apoptosis and atypical immune responses generated through the production of mitochondrial oxygen species (ROS). We demonstrated that immune cell ROS are produced at abnormally high levels in infants with severe NE and increase over the first week of life despite hypothermia therapy. Babies with NE, children aged 4-6years who had NE and age-matched controls will have inflammatory phenotyping to assess persistent immune dysregulation. Detailed 1.5T MRI, MRS and 3.0T MRI and neurological outcome will be correlated with these results. Mechanisms of persistent inflammation & immunomodulation: Exploring immune activation and persistent dysfunction is crucial in the development of new treatments for NE and brain injury and there are several potential targets including: Hypoxia-inducible factor(HIF-1)-alpha and succinate metabolism. HIF1a is a key transcription factor in the hypoxia response and as well as mitochondrial dysfunction and succinate accumulation is associated with persistent inflammation and may be a potential therapeutic target.

Conclusions: Understanding the function and metabolism of systemic inflammatory cells is important in the pathogenesis of neonatal brain injury to find relevant biomarkers of severity.

Last updated 21 December 2016 Web Administrator (Email).