Mechanisms and novel therapy in intrauterine inflammation induced brain injury

摘要/摘要：母体免疫激活与脑瘫等神经发育障碍的发生有关，但在了解母体炎症导致围产期脑损伤导致这些疾病的机制方面还存在基本的知识缺口。宫内炎症引起的犬尿氨酸途径引起的色氨酸代谢增加可能在这种损伤的发展中起关键作用。犬尿氨酸通路的激活不仅发生在胎盘中，也发生在胎儿和新生儿大脑中激活的小胶质细胞中，导致血清素消耗和神经毒性代谢物的产生。本应用的目的是进一步确定子宫内炎症诱导的胎盘和胎儿/新生儿大脑中色氨酸代谢和血清素消耗改变导致胎儿和新生儿脑损伤的作用。此外，我们将在产前和产后使用一种作用于犬尿氨酸途径的药物来测试治疗效果，通过抑制犬尿氨酸单加氧酶（KMO）来减少神经毒性代谢物3-羟基犬尿氨酸和喹啉酸的形成。对于产后治疗，该药物将使用新型的基于树突的纳米装置特异性地递送到新生儿大脑中激活的小胶质细胞。核心假设是宫内炎症激活胎盘和胎儿小胶质细胞中色氨酸代谢的犬尿氨酸途径，导致胎儿/新生儿大脑中持续的兴奋性毒性损伤和血清素消耗，抑制该途径可预防或逆转损伤。本研究的基本原理是了解母体宫内炎症诱导的犬尿氨酸通路激活对发育中的大脑的影响，将有助于确定针对抑制该通路的新治疗策略，以减轻胎儿和新生儿脑损伤。这些假设将通过以下具体目标进行检验：(1)确定子宫内炎症引起的胎盘和胎儿/新生儿脑色氨酸代谢异常；(2)确定母体抑制KMO是否会有效减少胎儿的神经炎症和脑损伤，改善新生儿的运动缺陷；(3)确定在产后使用新型树突纳米装置特异性递送KMO抑制剂到活化的小胶质细胞是否有效。将导致新生儿兔暴露于宫内炎症的持续损伤衰减。该研究具有创新性，因为(1)它针对犬尿氨酸途径预防/衰减胎儿和新生儿的脑损伤，(2)在新生儿中使用非侵入性正电子发射断层扫描成像来评估脑损伤的程度，并随时间跟踪治疗反应；(3)利用树突状分子在炎症部位的选择性定位，在产后发展治疗应用；(4)汇集了成像和纳米技术的独特发展转化应用。这项工作将更好地了解母体炎症诱导的犬尿氨酸通路激活对胎儿和新生儿脑损伤的影响，并将导致针对该通路的新的治疗策略，以减少围产期宫内炎症诱导的脑损伤。

DESCRIPTION (provided by applicant): 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.