Systemic biomarkers of brain injury from hyperammonemia

高氨血症脑损伤的全身生物标志物

• 批准号: 10015370
• 负责人: Nicholas Ah Mew
• 金额: $ 22.31万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10015370
• 关键词: Acute; Acute Brain Injuries; Address; Adult; Affect; Ammonia; Animal Model; Animals; Anisotropy; Astrocytes; Biological Markers; Blood; Blood Circulation; Brain; Brain Edema; Brain Injuries; Brain imaging; Cells; Cessation of life; Chemicals; Child; Chronology; Citrulline; Clinical; Clinical Trials; Clinical assessments; Coma; Cytotoxic Brain Edema; Development; Diffusion Magnetic Resonance Imaging; Evaluation; Exposure to; Fishes; Functional disorder; Future; Glutamates; Glutamine; Goals; Hospitalization; Hydrolase; Hyperammonemia; Hypoxic Brain Damage; Impairment; Intellectual functioning disability; Intervention; Knockout Mice; Laboratories; Lead; Light; Liver; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Metabolism; Modality; Monitor; Motor; N acetyl L glutamate; N-carbamylglutamate; Neurocognitive; Neurocognitive Deficit; Neuron-Specific Enolase; Neurons; Organ; Ornithine Carbamoyltransferase; Outcome Assessment; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Plasma; Plasma Proteins; Proteins; Recovery; Schools; Sensory; Severities; Social Development; Supplementation; Testing; Toxic effect; Traumatic Brain Injury; Ubiquitin; Urea cycle disorders; Water; Withdrawal; Zebrafish; axon injury; brain cell; cell injury; cohort; drug candidate; gray matter; imaging biomarker; imaging study; mental state; neuron loss; neurotoxicity; novel; pre-clinical; prevent; protein biomarkers; rare genetic disorder; response; tool; ubiquitin C-terminal hydrolase; white matter

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学因素， 这是一组罕见的遗传疾病，大约每35，000人中就有1人受到影响。HA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HA的治疗方法有 针对降低血氨水平;虽然他们可以防止脑水肿死亡，他们是 在减少或预防HA引起的脑损伤方面效率低下。去发现和开发治疗方法， 为了防止HA引起的脑损伤和/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种延长鱼类存活时间的化合物 暴露在高浓度的氨中，使鱼保持正常或接近正常的运动 对光暗周期的反应。这些候选药物在临床前和临床环境中的评价 需要经验证的生物标志物来监测HA引起的脑损伤。缺乏经验证的全身性生物标志物 可用于监测急性HA期间的脑损伤，这是寻求旨在 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.为了确定脑特异性蛋白质的血浆浓度是否与脑 受伤的HA。这些研究将用我们的诱导型HA的动物模型，即纯合的N- 乙酰谷氨酸合酶敲除（NAGSko）小鼠，其存活至成年并在 补充N-氨甲酰谷氨酸盐和瓜氨酸，并在停止补充时产生HA。 将在NAGSko小鼠中诱导HA，然后测量血浆氨、S100 B、神经元- 特异性烯醇化酶（NSE）和泛素C-末端水解酶L1（UCHL 1）在基线时，在急性HA和一个 从HA事件恢复后一周。2.为了确定S100 B、NSE和UCHL 1的浓度是否 与HA引起的脑损伤的定量MRI测量相关。我们将测量氨 S100 B，NSE和UCHL 1的血液中，并采用磁共振模式， 计算急性HA发作之前和期间的各向异性分数。3.描述的年代 S100 B，NSE和UCHL 1血液水平响应于受影响的UCD患者的HA脑损伤。我们将 在近端UCD患者中进行初步研究（鸟氨酸转氨甲酰酶或氨甲酰磷酸 合成酶1缺陷）以确定血浆S100 B、NSE和UCHL 1是否与血氨相关 在急性HA发作期间。拟议的研究将提供监测所需的经验证的生物标志物 急性HA引起的脑损伤。这些生物标志物对于衡量新干预措施的效果至关重要 旨在防止高浓度氨对大脑的损伤。