Systemic biomarkers of brain injury from hyperammonemia

高氨血症脑损伤的全身生物标志物

基本信息

  • 批准号:
    10015370
  • 负责人:
  • 金额:
    $ 22.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-10 至 2022-06-30
  • 项目状态:
    已结题

项目摘要

Abstract Hyperammonemia (HA) is the primary contributor of pathophysiology in the urea cycle disorders, which are a group of rare genetic diseases that affect approximately 1 in 35,000 people. HA can result in brain injury leading to irreversible intellectual and developmental disabilities, and even death. Current therapies for HA are targeted at reducing blood ammonia levels; although they can prevent death from brain edema, they are inefficient at reducing or preventing brain injury from HA. To discover and develop treatments that prevent brain injury from HA and/or promote recovery, we performed a phenotypic screen of >10,000 chemicals for the protection of zebrafish from ammonia toxicity and identified 16 compounds that prolonged the survival of fish exposed to high ammonia concentrations and allowed the fish to maintain normal, or close to normal locomotor response to light-dark cycle. Evaluation of these candidate drugs in both preclinical and clinical settings requires validated biomarkers for monitoring brain injury from HA. Absence of validated systemic biomarkers that can be used to monitor brain injury during acute HA is a major barrier in the search for therapies aimed at protecting brain from ammonia toxicity. This challenge will be addressed by the following proof-of-concept specific aims: 1. To determine whether plasma concentrations of brain-specific proteins correlate with brain injury from HA. These studies will be carried out with our animal model of inducible HA, the homozygous N- acetylglutamate synthase knockout (NAGSko) mouse that survives into adulthood and reproduces when supplemented with N-carbamylglutamate and citrulline, and develops HA when supplementation is withdrawn. HA will be induced in the NAGSko mice followed by measurements of plasma ammonia, S100B, neuron- specific enolase (NSE), and ubiquitin C-terminal hydrolase L1 (UCHL1) at baseline, during acute HA and one week after recovery from the HA episode. 2. To determine whether concentrations of S100B, NSE and UCHL1 in the blood correlate with quantitative MRI measurements of brain injury due to HA. We will measure ammonia S100B, NSE and UCHL1 in the blood of HA NAGSko mice, and employ magnetic resonance modalities to calculate fractional anisotropy before and during acute HA episode. 3. To characterize the chronology of S100B, NSE and UCHL1 blood levels in response to an HA brain insult in affected UCD patients. We will conduct a pilot study in patients with proximal UCD (either ornithine transcarbamylase or carbamylphosphate synthase 1 deficiencies) to determine whether plasma S100B, NSE and UCHL1 correlate with blood ammonia during an acute HA episode. The proposed studies will deliver the validated biomarkers required for monitoring brain injury from acute HA. These biomarkers will be essential for measuring the effects of novel interventions aimed at preventing brain injury from high ammonia concentrations.
摘要 高氨血症(HA)是尿素循环障碍的主要病理生理因素,尿素循环障碍是一种 一组罕见的遗传病,大约每35,000人中就有一人受到影响。透明质酸可导致脑损伤 导致不可逆转的智力和发育障碍,甚至死亡。目前治疗HA的方法有 旨在降低血氨水平;尽管它们可以防止死于脑水肿,但它们 在减少或预防HA引起的脑损伤方面效率低下。发现和开发预防的治疗方法 HA造成的脑损伤和/或促进恢复,我们对>10,000种化学物质进行了表型筛选 保护斑马鱼免受氨中毒,并确定了16种延长鱼类存活的化合物 暴露在高浓度的氨中,并允许鱼保持正常或接近正常的运动能力 对明暗循环的反应。这些候选药物在临床前和临床环境中的评估 需要经过验证的生物标记物来监测HA的脑损伤。缺乏有效的系统性生物标记物 可用于监测急性HA期间的脑损伤是寻找旨在 保护大脑免受氨中毒。这一挑战将通过以下概念验证来解决 具体目标:1.确定脑特定蛋白的血浆浓度是否与大脑相关 HA造成的伤害。这些研究将使用我们的诱导性HA动物模型-纯合子N-HA进行。 乙酰谷氨酸合成酶基因敲除(NAGSko)小鼠,成年期存活并在 补充N-氨基甲酰谷氨酸和瓜氨酸,并在停止补充时形成HA。 将在NAGSko小鼠中诱导HA,然后测定血氨、S100B、神经元- 特异烯醇化酶(NSE)和泛素C末端水解酶L1(UCHL1)在基线、急性HA和 从HA发作中恢复的一周后。2.确定S100B、NSE和UCHL1的浓度 与血液中HA引起的脑损伤的MRI定量测量相关。我们将测量氨气 HANAGSko小鼠血液中的S100B、NSE和UCHL1,并利用磁共振技术 计算急性HA发作前和发作期间的各向异性分数。3.描述……的年表 受影响的尿毒症患者对HA脑侮辱反应的S100B、NSE和UCHL1水平。我们会 对患有近端尿崩症(鸟氨酸转氨酶或氨基甲酸磷酸酯)的患者进行先导性研究 合酶1缺陷)以确定血浆S100B、NSE和UCHL1是否与血氨相关 在一次急性HA发作期间。拟议的研究将提供监测所需的经过验证的生物标志物 急性HA引起的脑损伤。这些生物标志物将是衡量新干预措施效果的关键 旨在防止高浓度氨造成的脑损伤。

项目成果

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Nicholas Ah Mew其他文献

Nicholas Ah Mew的其他文献

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{{ truncateString('Nicholas Ah Mew', 18)}}的其他基金

Expert curation of sequence variants in the proximal urea cycle genes
近端尿素循环基因序列变异的专家管理
  • 批准号:
    10630560
  • 财政年份:
    2023
  • 资助金额:
    $ 22.31万
  • 项目类别:
Identification of biomarkers for biochemical, pathophysiological and neurological effects of high ammonia concentration on the central nervous system in a preclinical model of neonatal hyperammonemia
在新生儿高氨血症临床前模型中鉴定高氨浓度对中枢神经系统生化、病理生理学和神经学影响的生物标志物
  • 批准号:
    10490324
  • 财政年份:
    2021
  • 资助金额:
    $ 22.31万
  • 项目类别:
Identification of biomarkers for biochemical, pathophysiological and neurological effects of high ammonia concentration on the central nervous system in a preclinical model of neonatal hyperammonemia
在新生儿高氨血症临床前模型中鉴定高氨浓度对中枢神经系统生化、病理生理学和神经学影响的生物标志物
  • 批准号:
    10302593
  • 财政年份:
    2021
  • 资助金额:
    $ 22.31万
  • 项目类别:
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