The long-term goal of the research is to understand the roles of inflammatory mediators in the pathogenesis of neonatal brain injury. The investigators' research focuses primarily on understanding how inflammation, initiated by acute ischemic brain injury, influences the ultimate expression of tissue damage, and how critical components of this inflammatory response can be modulated to improve neurological outcome. The primary hypothesis underlying this research proposal is that pro-inflammatory mediators play pivotal roles in determining the impact of hypoxic-ischemic insults on the developing brain. Experiments will be performed in well characterized neonatal rodent (rat and mouse) models of hypoxic-ischemic brain injury (unilateral carotid artery ligation + timed exposure to moderate hypoxia). The original research focus was on the role of the proinflammatory cytokine Interleukin-1beta in neonatal brain injury. Their findings in the initial funding period prompted them to broaden the scope of the work to include studies of several related pathogenetically relevant inflammatory mediators. They propose to delineate specific mechanisms of inflammation-mediated neuronal and oligodendroglial injury in the neonatal brain, and to determine if anti-inflammatory treatment interventions can reduce neonatal hypoxic-ischemic brain injury.
Aim 1 will focus on the pathogenetic roles of 2 beta-chemokines (monocyte chemoattractant protein-1 and monocyte inflammatory protein 1-alpha) and their cellular targets.
Aim 2 will evaluate the contribution of complement system activation in the brain in the pathogenesis of neonatal hypoxic-ischemic brain injury.
Aim 3 will evaluate the influence of pro-inflammatory mediators on the vulnerability of oligodendroglia to hypoxia-ischemia.
Aim 4 will evaluate the long-term outcome of anti-inflammatory interventions with respect to tissue integrity and behavioral measures. The proposed experiments could identify some of the critical cellular/molecular mechanisms in the acute post injury inflammatory cascade that determine the extent of neuronal and glial injury, and ultimately provide novel treatment approaches to improve long-term neuro-developmental outcome.
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