Mode of action of a neuroprotective compound

神经保护化合物的作用方式

• 批准号: 9234602
• 负责人: Corinne Ida Lasmezas
• 金额: $ 19.2万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234602
• 关键词: ADP ribosylation; Affinity; Aftercare; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Axotomy; Beta Carbolines; Biological Assay; Biotin; Brain; Brain Ischemia; Cell Survival; Cells; Chemicals; Consumption; Data; Degradation Pathway; Development; Disease; Enzymes; Family; Frontotemporal Dementia; Future; Genetic; Huntington Disease; Injury; Ion Channel; Knowledge; Label; Lead; Link; Mass Spectrum Analysis; Metabolism; Methods; Modeling; Molecular; Molecular Target; Mono-S; Morphology; Multiple Sclerosis; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Pharmacology; Preclinical Drug Evaluation; Prion Diseases; Prions; Proteins; Proteomics; Psychotropic Drugs; Reaction; Recombinants; Recovery; Reperfusion Injury; Research; Rodent Model; Role; Series; Structure; Structure-Activity Relationship; Testing; Toxic effect; Wallerian Degeneration; analog; base; carboxylate; excitotoxicity; experimental study; genetic manipulation; high throughput screening; injured; insight; motor function improvement; mouse model; neuroblastoma cell; neuron loss; new therapeutic target; overexpression; programs; protein misfolding; public health relevance; small molecule

 DESCRIPTION (provided by applicant): NAD+ depletion causes neuronal death in rodent models of brain ischemia/reperfusion injury, Wallerian degeneration, multiple sclerosis and occurs after excitotoxic insults and oxidative stress. We have recently discovered that NAD+ depletion is also the primary cause of neuronal death induced by a misfolded and toxic form of the amyloidogenic prion protein (TPrP). These results established the role of NAD+ depletion in the pathogenesis of at least one protein misfolding neurodegenerative disease, a family of diseases that comprise, among others, Alzheimer's disease and Parkinson's disease. NAD+ replenishment reversed the fate of TPrP- injured neurons in culture and improved motor function in a mouse model of prion disease. In a pilot high- throughput screen we identified a compound restoring neuronal viability by NAD+ replenishment in TPrP- exposed cells. We hypothesize that its molecular target is a key effector in the TPrP-induced pathway and that deciphering the compound's mode of action will further our understanding of the mechanisms of NAD+ depletion prevalent in TPrP toxicity and possibly other debilitating brain conditions. In this focused research effort, we will use affinity-based methods combined with proteomics to identify the compound's molecular target relevant to its neuroprotective activity, determine its mode of action and probe its structure for enhanced activity. This knowledge will provide insights into degenerative pathways linked to NAD+ depletion and will support lead development efforts aiming at developing a neuroprotective drug.

 描述(申请人提供)：在脑缺血/再灌注损伤、沃勒变性、多发性硬化症的啮齿动物模型中，NAD+耗竭会导致神经元死亡，并发生在兴奋性毒性侮辱和氧化应激之后。我们最近发现，NAD+耗竭也是导致神经元死亡的主要原因，这是由一种错误折叠的有毒形式的淀粉样蛋白蛋白(TPrP)引起的。这些结果证实了NAD+缺失在至少一种蛋白质错误折叠的神经退行性疾病的发病机制中所起的作用，该疾病家族包括阿尔茨海默病和帕金森病等。NAD+补充逆转了培养中TPrP损伤的神经元的命运，并改善了PrP病小鼠模型的运动功能。在中试高通量筛选中，我们确定了一种通过补充NAD+在TPrP暴露的细胞中恢复神经元活性的化合物。我们假设它的分子靶标是TPrP诱导的通路中的关键效应者，破译该化合物的作用模式将进一步了解TPrP中毒和其他衰弱大脑疾病中普遍存在的NAD+耗竭机制。在这项重点研究工作中，我们将使用基于亲和力的方法和蛋白质组学相结合的方法来确定与其神经保护活性相关的分子靶点，确定其作用模式，并探索其增强活性的结构。这些知识将提供对与NAD+衰竭有关的退化途径的洞察，并将支持旨在开发神经保护药物的领先开发努力。