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.

抽象的 高症血症（HA）是尿素周期疾病中病理生理学的主要因素，这是一个 一组罕见的遗传疾病影响了大约35,000人中的1人。 HA会导致脑损伤 导致不可逆转的智力和发展障碍，甚至导致死亡。 HA的当前疗法是 针对降低血液氨水的针对性；尽管它们可以防止大脑水肿死亡，但它们是 减少或防止HA的脑损伤效率低下。发现和开发预防的治疗 HA和/或促进恢复的脑损伤，我们对> 10,000种化学物质进行了表型筛查 保护斑马鱼免受氨毒性的侵害，并确定了16种延长鱼类存活的化合物 暴露于高氨浓度，并使鱼保持正常或接近正常运动 对光黑暗周期的响应。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期间脑损伤是寻找针对疗法的主要障碍 保护大脑免受氨毒性的侵害。以下概念证明将解决此挑战 具体目的：1。确定血浆特异性蛋白的血浆浓度是否与脑相关 HA受伤。这些研究将使用我们的诱导HA动物模型（纯合N-）进行 乙酰谷氨酸合酶基因敲除（Nagsko）小鼠，该小鼠在成年期生存并繁殖 补充N-核谷氨酸和瓜氨酸，并在撤回补充时会发展HA。 HA将在Nagsko小鼠中诱导，然后测量血浆氨，S100B，神经元 - 急性HA和1 HA情节恢复后一周。 2。确定S100B，NSE和UCHL1的浓度是否 在血液中，与HA引起的脑损伤的定量MRI测量相关。我们将测量氨 Ha Nagsko小鼠的血液中的S100B，NSE和UCHL1，并采用磁共振方式 在急性HA发作之前和期间计算分数各向异性。 3。表征的时间顺序 S100B，NSE和UCHL1血液水平响应受影响的UCD患者的HA脑侮辱。我们将 对近端UCD患者（鸟氨酸经钙化酶或氨基磷酸二磷酸酯的患者进行试验研究 合成酶1缺陷）确定血浆S100B，NSE和UCHL1是否与血液氨相关 在急性HA情节中。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脑损伤。这些生物标志物对于测量新干预的影响至关重要 旨在防止高氨浓度受到脑损伤。