Mechanisms and novel therapy in intrauterine inflammation induced brain injury

描述(申请人提供)：宫内炎症导致脑损伤的机制和新的治疗方法项目摘要/摘要母亲免疫激活与脑瘫等神经发育障碍的发展有关，但在理解围产期母体炎症导致脑损伤导致这些疾病的机制方面存在基本的知识差距。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生发展中起关键作用。犬尿氨酸途径的激活不仅发生在胎盘中，也存在于胎儿和新生儿脑中激活的小胶质细胞中，导致5-羟色胺耗竭和神经毒性代谢物的产生。这项应用的目的是进一步确定宫内炎症导致胎盘和胎儿/新生儿脑内色氨酸代谢改变和5-羟色胺耗竭，从而导致胎儿和新生儿脑损伤的作用。此外，我们将测试一种作用于犬尿氨酸途径的药物在产前和出生后的治疗效果，以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。对于出生后治疗，该试剂将使用基于树枝状大分子的新型纳米设备专门输送到新生儿大脑中激活的小胶质细胞。中心假说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/新生儿脑内持续的兴奋性毒性损伤和5-羟色胺的耗竭，抑制这一途径将导致损伤的预防或逆转。这项研究的基本原理是，了解母体宫内炎症导致犬尿氨酸途径激活对发育中大脑的影响，将有助于确定针对抑制该途径以减轻胎儿和新生儿脑损伤的新的治疗策略。这些假说将通过下列特定目标进行验证：(1)确定由宫内炎症引起的胎盘和胎儿/新生儿脑内色氨酸代谢的异常；(2)确定母亲抑制KMO是否将有效地减少胎儿的神经炎症和脑损伤，从而改善新生儿的运动缺陷；以及(3)确定在出生后阶段使用新型树枝状大分子纳米设备对激活的小胶质细胞特异性地给予KMO抑制剂是否将导致减轻暴露于宫内炎症的新生兔的持续损伤。这项拟议的研究之所以具有创新性，是因为(1)它针对犬尿氨酸途径，以预防/减轻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，并跟踪随时间推移的治疗反应；以及(3)利用树枝状大分子在炎症部位的选择性定位，开发出生后的治疗应用；(4)将成像和纳米技术的独特发展整合到翻译应用中。这项工作将有助于更好地了解母体炎症诱导的犬尿氨酸途径激活对胎儿和新生儿脑损伤的影响，并将针对这一途径提出新的治疗策略，以减轻围产期宫内炎症所致脑损伤。

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.