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：
Nicholas Ah Mew
金额：
$ 22.31万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
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

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

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.

抽象的高氨血症 (HA) 是尿素循环障碍病理生理学的主要原因，尿素循环障碍是一种一组罕见的遗传疾病，影响大约三万五千分之一的人。 HA可能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的治疗方法有旨在降低血氨水平；虽然它们可以防止因脑水肿而死亡，但它们无法有效减少或预防 HA 造成的脑损伤。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，我们对超过 10,000 种化学物质进行了表型筛选保护斑马鱼免受氨毒性，并鉴定出 16 种可延长鱼类存活时间的化合物暴露于高氨浓度下并使鱼保持正常或接近正常运动对光暗循环的反应。在临床前和临床环境中评估这些候选药物需要经过验证的生物标志物来监测 HA 造成的脑损伤。缺乏经过验证的全身生物标志物可用于监测急性 HA 期间脑损伤的方法是寻找治疗方法的主要障碍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. 确定大脑特异性蛋白质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型 HA 动物模型（纯合 N- 乙酰谷氨酸合酶敲除 (NAGSko) 小鼠可存活至成年并在以下情况下繁殖：补充 N-氨甲酰谷氨酸和瓜氨酸，并在停止补充时产生 HA。 HA 将在 NAGSko 小鼠中被诱导，然后测量血浆氨、S100B、神经元特异性烯醇化酶 (NSE) 和泛素 C 末端水解酶 L1 (UCHL1) 在基线、急性 HA 期间和一次从 HA 发作中恢复一周后。 2. 确定S100B、NSE和UCHL1的浓度是否血液中的含量与 HA 引起的脑损伤的定量 MRI 测量结果相关。我们将测量氨 HA NAGSko 小鼠血液中的 S100B、NSE 和 UCHL1，并采用磁共振方式计算急性 HA 发作之前和期间的各向异性分数。 3. 描述时间顺序受影响的 UCD 患者对 HA 脑损伤的反应的 S100B、NSE 和 UCHL1 血液水平。我们将对近端 UCD 患者进行初步研究（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 S100B、NSE 和 UCHL1 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。这些生物标志物对于衡量新型干预措施的效果至关重要旨在防止高氨浓度造成的脑损伤。