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NEBULA study: NEonatal brain Injury: Understanding systemic InfLAmmation & immunomodulation (2013-7)

PI: E Molloy

Collaborators: Professor William Watson, Dr Amanda O'Neill, Dr. Veronica Donoghue, Drs. Eoghan Mooney & Paul Downey, Prof Geraldine Boylan, Prof Bryan Lynch, Dr. Eva Jiminez, Dr. Denise McDonald, Dr. Suzanne Kelleher and Dr. John Kelleher

PhD student: Dr. Saima Aslam

Institutions: NMH, UCD, TCD, RCSI, UCC

Background: Neonatal brain injury has multifactorial etiology and causes significant neurological morbidity such as cerebral palsy. Therapeutic hypothermia is the only treatment available in term infants with neonatal encephalopathy (altered neurological function). Activated leucocytes, infection and persistent inflammation have been implicated in the pathogenesis of brain injury and cerebral palsy.

Circadian Rhythm and Melatonin: Circadian rhythm plays a key role in innate immune responses and melatonin is an essential regulator. Melatonin has been shown to improve outcomes in combination with hypothermia in animal models of neonatal brain injury. We will explore the mechanism underlying the altered activation of neutrophils and monocytes in neonates with brain injury by examining Circadian rhythm and the use of melatonin for neuroprotection. The key regulators of circadian rhythm BMAL-1 and CRY will be measured in infants with NE and neonatal controls. Persistent Inflammation and Circadian Rhythm: Hypoxia-inducible factor (HIF) 1 alpha is a key transcriptional factor in the hypoxic response and is associated with persistent inflammation. We will examine the role of the hypoxia inducible factor (HIF1 alpha) in persistent or sustained inflammation in NE. We will examine HIF 1 alpha expression in innate immune cells as well as modulation by melatonin.

Conclusion: MRI, clinical and neurodevelopmental outcome will be correlated with circadian rhythm as well as multi-organ dysfunction. This research will improve the understanding of the systemic inflammatory response in infants with brain injury and the potential for therapies such as melatonin in addition to hypothermia.


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