High-throughput screening assay development for axonopathic neurodegeration

轴突性神经变性的高通量筛选试验开发

• 批准号: 7169331
• 负责人: NORBERT PERRIMON
• 金额: $ 21.19万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7169331
• 关键词: NIH Roadmap Initiative tag; RNA interference; amyloid proteins; biomarker; chemical registry /resource; disease /disorder model; double stranded RNA; drug discovery /isolation; gene expression; high throughput technology; neural degeneration; neuronal transport; tissue /cell culture

DESCRIPTION (provided by applicant): Many neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), lead to the irreversible destruction of neuronal axons. Once axons are destroyed, there is no mechanism left for neuronal signaling, thus a drastic reduction of brain capacity occurs. It is known that the degeneration of axons is an active process that is controlled by the neuron itself. In addition, it is known that if transport of proteins and organelles along axons is slowed, this process of axonal self-destruction is stimulated. Very little is known about the exact mechanisms that control axonal degeneration and its link to disrupted axon transport. However there are excellent markers of axon transport that can be used to characterize axon transport-associated degeneration. One of these markers is amyloid precursor protein (APP), which is found in axonal aggregates from neurodegeneration pathology specimens. This proposal seeks to design high-throughput screens that will find genetic modifiers of axon transport, and drug compound modifiers of APP-associated axonal degeneration. The long term goal of this work is thus to understand better the causes of axonal destruction in neurodegenerative diseases, and to find drugs that can slow or prevent axonal degeneration from occurring.

描述（由申请人提供）：许多神经退行性疾病，例如阿尔茨海默氏病、多发性硬化症和肌萎缩侧索硬化症（ALS），会导致神经元轴突的不可逆破坏。一旦轴突被破坏，就没有神经元信号传递的机制，因此大脑容量会急剧下降。众所周知，轴突的退化是一个由神经元本身控制的主动过程。此外，众所周知，如果蛋白质和细胞器沿轴突的运输减慢，就会刺激轴突自我毁灭的过程。关于控制轴突变性的确切机制及其与轴突运输中断的联系知之甚少。然而，有一些优秀的轴突运输标记物可用于表征轴突运输相关的退化。这些标记物之一是淀粉样前体蛋白（APP），它存在于神经退行性病理标本的轴突聚集体中。该提案旨在设计高通量筛选，以找到轴突运输的遗​​传修饰剂和 APP 相关轴突变性的药物化合物修饰剂。因此，这项工作的长期目标是更好地了解神经退行性疾病中轴突破坏的原因，并找到可以减缓或预防轴突变性发生的药物。