Mechanisms and novel therapy in intrauterine inflammation induced brain injury Project summary/abstract Maternal immune activation has been implicated in the development of neurodevelopmental disorders such cerebral palsy, but there is a fundamental knowledge gap in understanding the mechanisms by which maternal inflammation results in brain injury in the perinatal period leading to these disorders. Increased tryptophan metabolism by the kynurenine pathway induced by intrauterine inflammation may play a crucial role in the development of this injury. Activation of the kynurenine pathway occurs not only in placenta but also in activated microglia in the fetal and neonatal brain, resulting in serotonin depletion and production of neurotoxic metabolites. The objective of this application is to further define the role of intrauterine inflammation induced alterations in tryptophan metabolism and serotonin depletion in the placenta and fetal/newborn brain resulting in brain injury in the fetus and neonate. In addition, we will test therapeutic efficacy in the prenatal and postnatal period using an agent acting on the kynurenine pathway, in order to decrease the formation of the neurotoxic metabolites 3-hydroxykynurenine and quinolinic acid by inhibiting the enzyme kynurenine mono- oxygenase (KMO). For postnatal therapy, the agent will be delivered specifically to activated microglia in the newborn brain using novel dendrimer-based nanodevices. The central hypothesis is that intrauterine inflammation activates the kynurenine pathway of tryptophan metabolism in the placenta and in fetal microglia, resulting in ongoing excitotoxic injury and serotonin depletion in the fetal/neonatal brain, and inhibition of this pathway will cause prevention or reversal of the injury. The rationale for this research is that understanding the effect of maternal intrauterine inflammation induced activation of the kynurenine pathway on the developing brain, will help in identifying novel therapeutic strategies targeted towards inhibition of this pathway for attenuation of fetal and neonatal brain injury. These hypotheses will be tested by the following specific aims: (1) Identify abnormalities in tryptophan metabolism in the placenta, and fetal/neonatal brain induced by intrauterine inflammation, (2) Determine whether maternal inhibition of KMO will effectively decrease neuroinflammation and brain injury in the fetus with improvement in motor deficits in the neonate, and (3) Determine if delivery of the KMO inhibitor specifically to activated microglia using novel dendrimer-based nanodevices in the postnatal period, will result in attenuation of ongoing injury in the neonatal rabbit exposed to intrauterine inflammation. The proposed research is innovative because (1) it targets the kynurenine pathway for prevention/attenuation of brain injury in the fetus and neonate and (2) uses non-invasive positron emission tomography imaging in the neonate for assessment of the extent of brain injury and to follow the therapeutic response over time;and (3) takes advantage of the selective localization of dendrimers at sites of inflammation, to develop therapeutic applications in the postnatal period;(4) brings together unique developments in imaging and nanotechnology for translational applications. This work will provide a better understanding of the effect of maternal inflammation induced activation of the kynurenine pathway on fetal and neonatal brain injury, and will lead to novel therapeutic strategies directed towards this pathway for attenuation of intrauterine inflammation induced brain injury in the perinatal period.
The proposed research is relevant to public health because it provides a better understanding of the role of maternal infection and inflammation in the pathogenesis of neurodevelopmental disorders such as cerebral palsy that would enable the development of specific targeted therapy for prevention of these disorders. Injury to the developing brain results in neurodevelopmental disorders that are often chronic resulting in debilitating disabilities, with large life time health care costs and very little treatment options. Understanding the mechanisms of these diseases and designing targeted therapy using this knowledge will benefit a large number of affected children. The works uses a translational research approach using a multidisciplinary group. Therefore, this work is relevant to NICHD's mission to ensure that every person in born healthy and that all children are able to remain free of disabilities.
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