Mission:
The Zaghloul lab investigated mechanism of neonatal brain injury and developing  targeted therapeutics.
The brain is the most energetically demanding organ of the body especially in premature infants. Premature infants are at increased risk of Periventricular leukomalacia (PVL) which is caused by hypoxic ischemic (HI) to the brain. HI causes an abrupt decline of brain’s fuel supply and mitochondrial generation of ATP. PVL further leads to neuronal death, hypomyelination and microglial activation. PVL is the most common cause of cerebral palsy in premature infant.
Targeted therapeutics for PVL at our lab mainly inhibit microglial activation while restoring mitochondrial integrity and function.
 

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Premature infants are susceptibility to develop HI due to the pressure-passive circulation without autoregulation and the susceptibility of premyelinating oligodendrocytes (pre-OLs) to both reactive oxidative (ROS) and nitrative stress (RNS) and excitotoxicity caused by accumulation of injurious extracellular glutamate. Preterm infants have deficient antioxidant system. Infection and/or systemic inflammation, which are seen in neonates born with chorioamnionitis induce a systemic increase in pro-inflammatory cytokines. Microglia activation causes the release of pro-inflammatory cytokines and free radicals leading to pre-OLs loss and maturation arrest. This in turn leads to mitochondrial dysfunction and ATP loss.

 

The Zaghloul Group focuses on the role of microglial activation, inflammation, oxidative stress and mitochondrial dysfunction that acts synergistically to cause PVL.

By inhibiting microglial activation through various drug therapies, anti-inflammatory state, energy metabolism and redox homeostasis will be restored thus preventing ongoing degeneration and promoting regeneration. By developing novel preclinical animal models and testing anti-microglial therapeutics will soon translate to human clinical trials.

 

The Zaghloul lab established a neonate mouse HI model mimicking human PVL in symptomatology, pathogenesis, molecular and cellular mechanism and long term neurodevelopmental aspects. This model develops diplegia and cerebral palsy. It also mimics human PVL autopsy specimens in histopathology showing white matter loss leading to ventriculomegally, neuronal apoptosis, astrogliosis and microglial activation. Our animal model also survives long beyond the HI injury, allowing better long term monitoring.

We have discovered that using various drugs that inhibit microglial activation can lead to white matter regeneration and reversal of neuronal apoptosis.

 

Research Specialist Senior and Lab Manger

Research Specialist Senior

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