Acute brain injury and blood-brain barrier dysfunction in cerebral malaria (ABC)

脑型疟疾(ABC)中的急性脑损伤和血脑屏障功能障碍

基本信息

项目摘要

ABSTRACT Cerebral malaria (CM) is an acute neurologic complication of infection with Plasmodium falciparum malaria that presents clinically as an unarousable coma. In CM, several pathogenic mechanisms interact to cause the characteristic neurocognitive sequelae observed in a quarter of surviving children. Infected erythrocytes sequester in the brain microvasculature leading to widespread inflammation, endothelial activation, hypoxic/ischemic injury, glucose abnormalities, hemolysis and cellular injury, resulting blood-brain barrier (BBB) dysfunction, which may interact to cause brain injury. We have found that elevated tau and other markers of injury to neurons are elevated in blood circulation and associated persistent neurodisability in survivors of CM. Further, these brain injury markers are associated with factors involved in the pathogenesis of CM, including glucose abnormalities, cellular injury, and endothelial/BBB dysfunction. What remains unclear is how intraerythrocytic parasites confined within the vascular space, cause injury to neurons without crossing the BBB. Thus, there is a critical need for mechanistic studies to define interactions between factors involved in the pathogenesis of CM leading to BBB dysfunction and neuronal injury. Animal and in-vitro BBB models have been key in advancing our knowledge of CM pathogenesis but limitations of existing models include: 1) interspecies variability of non-falciparum animal models, 2) use of endothelial monolayers that lack key components of the brain parenchyma, 3) reliance on immortalized or primary brain microvascular endothelial cell (BMECs) that lack physiologically relevant barrier properties and/or suffer from batch-to-batch variability. To overcome these limitations, we have developed a multicellular BBB model comprised of human-derived BMECs, neurons, and astrocytes. Using our multicellular BBB model, we propose to investigate neuronal injury and examine interactions between factors involved in CM pathogenesis and biomarkers of brain injury. And we will validate our brain injury biomarker data in a follow-up cohort of children with CM tested for cognitive impairments at 12- months. We hypothesize that sequestration of IEs to BMECs results in BBB dysfunction and the subsequent decrease of glucose availability and release of cellular injury marker lactate dehydrogenase (LDH) causing neuronal injury, which is a predictor of persistent neurodisability in clinical CM. Our hypothesis will be testing by the following specific aims: 1) evaluation of the impact of glucose deprivation, cellular injury, and endothelial dysfunction on neuronal injury in an in vitro human-derived multicellular BBB model, and 2) evaluation of a panel of brain injury biomarkers as predictors of neurodisability in clinical CM. Upon completion, this work will establish our human-derived multicellular BBB model as the standard for investigating mechanisms underlying neuronal injury, which we have shown to be a predictor of persistent neurodisability in clinical CM. Our model has the potential to transform the field of in-vitro CM neuropathology by facilitating research into new therapeutic targets to prevent or reduce future neurodisability after pediatric CM.
摘要 脑型疟疾(CM)是恶性疟原虫疟疾感染的急性神经系统并发症, 临床表现为无法唤醒的昏迷在CM中,几种致病机制相互作用, 在四分之一的存活儿童中观察到典型的神经认知后遗症。感染红细胞 隔离在脑微血管系统中,导致广泛的炎症,内皮激活, 缺氧/缺血性损伤、葡萄糖异常、溶血和细胞损伤,导致血脑屏障(BBB) 功能障碍,可能相互作用导致脑损伤。我们已经发现,tau蛋白和其他标志物的升高, 在CM的幸存者中,神经元的损伤在血液循环中升高,并与持续的神经功能障碍相关。 此外,这些脑损伤标志物与涉及CM发病机制的因素相关,包括 葡萄糖异常、细胞损伤和内皮/BBB功能障碍。目前尚不清楚的是 局限于血管空间内的红细胞内寄生虫在不穿过BBB的情况下对神经元造成损伤。 因此,迫切需要进行机制研究,以确定参与这些机制的因素之间的相互作用。 CM的发病机制导致BBB功能障碍和神经元损伤。动物和体外血脑屏障模型已经被 关键是提高我们对CM发病机制的认识,但现有模型的局限性包括:1)种间 非恶性疟原虫动物模型的可变性,2)使用缺乏关键成分的内皮单层, 脑实质,3)依赖于永生化或原代脑微血管内皮细胞(BMEC), 生理相关的阻隔性能和/或遭受批次间的变化。克服这些 限制,我们已经开发了一种多细胞血脑屏障模型,包括人源性BMEC,神经元, 星形胶质细胞利用我们的多细胞血脑屏障模型,我们建议研究神经元损伤和检查 参与CM发病机制的因素与脑损伤生物标志物之间的相互作用。我们会验证 我们在12岁时进行认知障碍测试的CM儿童随访队列中的脑损伤生物标志物数据, 个月我们假设,隔离的IE BMEC的结果在BBB功能障碍和随后的 葡萄糖利用率的降低和细胞损伤标志物乳酸脱氢酶(LDH)的释放, 神经元损伤,这是临床CM中持续性神经残疾的预测因子。我们的假设将通过 具体目的如下:1)评价葡萄糖剥夺、细胞损伤和内皮细胞损伤的影响。 在体外人源性多细胞BBB模型中对神经元损伤的功能障碍的评估,和2)评估一组 脑损伤生物标志物作为临床CM中神经功能障碍的预测因子。完成后,这项工作将建立 我们的人源性多细胞血脑屏障模型作为研究神经元机制的标准 损伤,我们已经证明这是一个预测的持续性神经功能障碍的临床CM。我们的模型具有 通过促进研究新的治疗靶点,有可能改变体外CM神经病理学领域 预防或减少儿童CM后的未来神经功能障碍。

项目成果

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Scott G Canfield其他文献

Scott G Canfield的其他文献

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{{ truncateString('Scott G Canfield', 18)}}的其他基金

Acute brain injury and blood-brain barrier dysfunction in cerebral malaria (ABC)
脑型疟疾(ABC)中的急性脑损伤和血脑屏障功能障碍
  • 批准号:
    10433313
  • 财政年份:
    2022
  • 资助金额:
    $ 14.72万
  • 项目类别:

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