Acute injury to the brain is followed by tissue repair processes. Whether the injury ultimatelyresults in a functional deficit likely depends on factors such as the effectiveness of the repairprocesses, the affected area(s) of the brain, and the extent of the initial injury. The presentproject will focus on the repair process in two distinct models of neonatal brain injury - neonatalbacterial meningitis and transient middle cerebral artery (MCA) occlusion. The two models sharecommon features during the acute phase, such as tissue inflammation and apoptotic neuronalcell death; very little is known about the repair process in these models.Bacterial meningitis consistently leads to hippocampal injury characterized by death of newlyformed neurons with long lasting or permanent learning deficits. This injury is relatively mild,preserving the architecture of the affected area. The dentate gyrus is a site of continuousformation of new neurons and therefore potentially well equipped for repair. Acute MCAocclusion, on the other hand, often leads to severe structural injury to cortical and subcorticalregions with tissue necrosis. Thus, this model represents a paradigm with more limitedregeneration capacities, which is likely to pose major hurdles to improvement of repairprocesses.The main hypothesis to be explored is that the repair processes after neonatal brain injury areinhibited by inflammatory mediators and enhanced by matrix metalloproteinases (MMPs).
Our specific aims to address this hypothesis are:
Aim 1. To determine whether inflammatorymediators exert an inhibitory effect on tissue repair processes after neonatal brain injury.
Aim 2. To test whether MMPs exert a beneficial role in the repair process after neonatal brain injury Aim3. To assess whether tissue repair improves functional outcome. The goal of this work is todevelop strategies aimed at maximizing the repair process and minimizing the long termfunctional deficits in a disease-adapted way.
TO HUMAN HEALTH: This proposedwork is important since attempts to reduce acute brain injury due to ischemia or meningitis inyoung children have thus far been met with limited success.
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