Mechanisms and novel therapy in intrauterine inflammation induced brain injury

宫内炎症引起的脑损伤的机制和新疗法

• 批准号: 8609500
• 负责人: Sujatha Kannan
• 金额: $ 32.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8609500
• 关键词: Acetylcysteine; Address; Affect; Age; Amniotic Fluid; Animal Model; Astrocytes; Attenuated; Biocompatible; Biological Availability; Birth; Brain; Brain Injuries; Cerebral Palsy; Child; Chronic; Dendrimers; Development; Dioxygenases; Disease; Dose; Drug Delivery Systems; Endotoxins; Ensure; Enzymes; Fetus; Goals; Health Care Costs; Image; Infection; Inflammation; Injury; Knowledge; Kynurenic Acid; Kynurenine; Kynurenine 3-monooxygenase; Lead; Life; Metabolic; Microglia; Mission; Mono-S; N-Methylaspartate; Nanotechnology; Neonatal; Neonatal Brain Injury; Neurodevelopmental Disorder; Neuronal Injury; Newborn Infant; Oryctolagus cuniculus; Oxygenases; Pathogenesis; Pathway interactions; Perinatal; Perinatal Brain Injury; Persons; Pharmacological Treatment; Phenotype; Placenta; Play; Polymers; Positron-Emission Tomography; Prevention; Prevention therapy; Production; Public Health; Quinolinic Acid; Reporting; Research; Role; Serotonin; Site; Somatosensory Cortex; Testing; Therapeutic; Time; Tracer; Translational Research; Treatment Efficacy; Tryptophan; Tryptophan Metabolism Pathway; Up-Regulation; Work; abstracting; attenuation; base; benzenesulfonamide; design; disability; disorder prevention; fetal; immune activation; improved; in utero; indoleamine; inhibitor/antagonist; innovation; motor deficit; multidisciplinary; myelination; nanodevice; nanostructured; neonate; neuroinflammation; neurotoxic; novel; novel therapeutics; postnatal; prenatal; response; therapeutic target

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.

描述（由申请人提供）：宫内炎症诱导脑损伤的机制和新疗法项目摘要/摘要母体免疫激活与神经发育障碍如脑瘫的发展有关，但在理解母体炎症导致围产期脑损伤从而导致这些障碍的机制方面存在基本的知识差距。子宫内炎症引起的犬尿氨酸途径的色氨酸代谢增加可能在这种损伤的发展中起着至关重要的作用。犬尿氨酸途径的激活不仅发生在胎盘中，也发生在胎儿和新生儿脑中的活化小胶质细胞中，导致5-羟色胺耗竭和神经毒性代谢产物的产生。本申请的目的是进一步确定子宫内炎症诱导的胎盘和胎儿/新生儿脑中色氨酸代谢和5-羟色胺耗竭的改变导致胎儿和新生儿脑损伤的作用。此外，我们将使用作用于犬尿氨酸途径的药剂测试产前和产后时期的治疗功效，以便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，该药物将使用基于新型树枝状聚合物的纳米装置特异性地递送到新生儿大脑中的活化小胶质细胞。中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/新生儿脑中持续的兴奋性毒性损伤和5-羟色胺耗竭，抑制该途径将导致损伤的预防或逆转。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大脑的影响，将有助于确定针对抑制该通路以减轻胎儿和新生儿脑损伤的新型治疗策略。这些假设将通过以下具体目标进行检验：（1）鉴定胎盘中色氨酸代谢的异常，以及宫内炎症诱导的胎儿/新生儿脑，（2）确定母体抑制KMO是否将有效减少胎儿的神经炎症和脑损伤，并改善新生儿的运动缺陷，和（3）确定在出生后时期使用基于新型树枝状聚合物的纳米装置将KMO抑制剂特异性递送至活化的小胶质细胞是否会导致暴露于子宫内炎症的新生兔中正在进行的损伤的减弱。拟议的研究是创新的，因为（1）它靶向犬尿氨酸途径，用于预防/减轻胎儿和新生儿的脑损伤，以及（2）在新生儿中使用非侵入性正电子发射断层扫描成像，用于评估脑损伤的程度，并随时间推移跟踪治疗反应;和（3）利用树枝状聚合物在炎症部位的选择性定位，以开发出生后时期的治疗应用;（4）汇集了成像和纳米技术的独特发展，用于转化应用。这项工作将提供一个更好的理解母体炎症诱导激活犬尿氨酸途径对胎儿和新生儿脑损伤的影响，并将导致新的治疗策略，针对这一途径的衰减宫内炎症诱导的脑损伤在围产期。