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Neuroprotection from hyperammonemia: small molecule screen

高氨血症的神经保护：小分子筛选

基本信息

批准号：
8670740
负责人：
Ljubica Morizono Caldovic
金额：
$ 21.5万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8670740
关键词：
Acute Ammonia Astrocytes Biochemical Biological Factors Biological Markers Blood Brain Brain Edema Brain Injuries Cessation of life Chronic Citrulline Classification Cognitive deficits Coma Convulsions Cyclic GMP Data Defect Development Disease Dose FDA approved Fishes Gene Expression Genetic Models Glutamate-Ammonia Ligase Glutamine Goals Human Hyperammonemia Inborn Errors of Metabolism Intellectual functioning disability Investigational Drugs Knock-out Knockout Mice Larva Lead Lethal Dose 50 Libraries Life Liver Liver Failure Mammals Measures Mediating Methionine Sulfoximine Methods Modeling Molecular Molecular Profiling Mus N-Methyl-D-Aspartate Receptors N-carbamylglutamate Nervous System Trauma Neuraxis Neurologic Neurons Neuroprotective Agents Outcome Pathway interactions Patients Pharmaceutical Preparations Preclinical Drug Evaluation Reporting Research Rewards Signal Transduction Staging Stress Testing Toxic effect Validation Water Zebrafish ammonium acetate base combinatorial design drug discovery drug testing falls high risk high throughput screening improved in vivo insight intellectual and developmental disability mouse model neuroprotection neurotoxicity novel prevent protective effect public health relevance research study screening small molecule small molecule libraries urea cycle

项目摘要

DESCRIPTION (provided by applicant): Hyperammonemia caused either by inborn errors of metabolism, liver failure or extreme catabolic stress can be life threatening and can cause severe brain damage resulting in intellectual and developmental disabilities. Available therapies are mainly targeted at reducing blood ammonia levels and although they can fervent death from brain edema, they are inefficient at reducing or preventing brain damage. Here we propose to develop novel treatment aimed at protecting the brain from elevated levels of blood ammonia. The proposed studies will use zebrafish and mouse models of hyperammonemia to screen and validate small molecules for their ability to provide neuroprotection from hyperammonemia. In addition, biomarkers for hyperammonemia will be explored in zebrafish to gain insights into the mechanisms of neuroprotection afforded by selected small molecules. The specific aims are: 1. To identify small molecules that afford protection from ammonia using a 2- stage screen in zebrafish and NAGSko mice. This aim will be accomplished by high throughput screening of small molecule libraries in zebrafish exposed to hyperammonemia followed by validation of effective molecules in a mouse genetic model of hyperammonemia (NAGSko). 2. To establish biochemical and molecular biomarkers of hyperammonemia in zebrafish. This aim will use biochemical and gene expression methods in zebrafish to gain insights into the mechanisms of hyperammonemia and how protective molecule exert their effects on the brain in the context of these mechanisms. Overall, this exploratory project takes a new direction in tackling the devastating effects of hyperammonemia. If successful, drugs that result from this projects would be complementary to current treatment approaches eventually improving the outcome of patients with hyperammonemia.

描述（由申请人提供）：由先天性代谢缺陷、肝功能衰竭或极端分解代谢应激引起的高氨血症可能危及生命，并可能导致严重的脑损伤，导致智力和发育残疾。现有的治疗方法主要针对降低血氨水平，尽管它们可以导致脑水肿死亡，但它们在减少或预防脑损伤方面效率低下。在这里，我们建议开发新的治疗方法，旨在保护大脑免受血氨水平升高的影响。拟议的研究将使用高氨血症的斑马鱼和小鼠模型来筛选和验证小分子提供高氨血症神经保护的能力。此外，将在斑马鱼中探索高氨血症的生物标志物，以深入了解所选小分子提供的神经保护机制。具体目标是：1.在斑马鱼和NAGSko小鼠中使用2阶段筛选鉴定提供氨保护的小分子。这一目标将通过高通量筛选暴露于高氨血症的斑马鱼中的小分子文库，然后在高氨血症的小鼠遗传模型（NAGSko）中验证有效分子来实现。2.建立斑马鱼高氨血症的生化和分子生物学标志物。该目标将使用斑马鱼的生物化学和基因表达方法来深入了解高氨血症的机制以及保护性分子如何在这些机制的背景下对大脑发挥作用。总的来说，这个探索性项目为解决高氨血症的破坏性影响提供了新的方向。如果成功，该项目产生的药物将补充目前的治疗方法，最终改善高氨血症患者的结局。