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（由申请人提供）：NAD+耗竭导致啮齿类动物脑缺血/再灌注损伤、沃勒变性、多发性硬化症模型中的神经元死亡，并在兴奋性毒性损伤和氧化应激后发生。我们最近发现NAD+耗竭也是神经元的主要原因。由错误折叠且有毒的淀粉样朊病毒蛋白 (TPrP) 诱导的死亡这些结果证实了 NAD+ 的作用。在神经退行性疾病（包括阿尔茨海默病和帕金森病等在内的一系列疾病）的发病机制中，补充 NAD+ 可以逆转培养物中 TPrP 损伤的神经元的命运，并改善小鼠模型的运动功能。在一项试验性高通量筛选中，我们发现了一种通过补充 TPRP 细胞中的 NAD+ 来恢复神经活力的化合物，我们发现其分子靶标是关键。 TPrP 诱导途径中的效应子，破译该化合物的作用模式将进一步了解 TPrP 毒性和可能的​​其他使人衰弱的大脑疾病中普遍存在的 NAD+ 消耗机制。在这项重点研究工作中，我们将结合使用基于亲和力的方法。通过蛋白质组学来识别该化合物与其神经保护活性相关的分子靶标，确定其作用模式并探索其结构以增强活性，这些知识将为了解与 NAD+ 相关的退化途径提供见解。耗尽并将支持旨在开发神经保护药物的先导开发工作。