Neuroprotective drugs for A-T

A-T 神经保护药物

• 批准号: 8616449
• 负责人: DAVID WASSARMAN
• 金额: $ 22.17万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616449
• 关键词: ATM gene; ATM wt Allele; Age; Animal Model; Animals; Ataxia; Ataxia Telangiectasia; Biological Assay; Blood - brain barrier anatomy; Cell Cycle; Cell physiology; Cells; Cerebellar Ataxia; Cerebellum; Clinic; Clinical; Collection; Dependence; Development; Disease; Drosophila genus; Drosophila melanogaster; Eating; Event; Eye; Food; Goals; Hereditary Disease; Human; Human Development; Immune response; Longevity; Measures; Modeling; Molecular; Motor; Mutate; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Neuroprotective Agents; Normal Cell; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiology; Preclinical Drug Evaluation; Probability; Property; Research; Testing; Therapeutic; Toxic effect; Wheelchairs; drug discovery; effectiveness measure; expectation; fly; human disease; mutant; novel; pre-clinical; prevent; progressive neurodegeneration; public health relevance; therapeutic target; therapy development

DESCRIPTION (provided by applicant): We propose to identify drugs that prevent neurodegeneration in the human disease Ataxia-telangiectasia (A-T). A-T is a rare genetic disease characterized by ataxia, a lack of motor coordination. Neurodegenerative events in the cerebellum that bring about the ataxia begin before the age of two and get worse with age, resulting in wheelchair dependence between the ages of eight and twelve. Research into the causes of neurodegeneration began in earnest in 1995 when the defective gene A-T mutated (ATM) was identified. However, despite considerable progress in understanding ATM functions in normal cells and cellular processes that are dysregulated in ATM mutant cells, no therapies have been developed that prevent neurodegeneration. A major barrier to the development of therapies has been the lack of animal models of A-T that undergo neurodegeneration. We have created fruit fly (Drosophila melanogaster) models of A-T. The fly models recapitulate the progressive neurodegeneration that occurs in A-T patients. Using these models, we have developed assays that can serve to measure the effectiveness of drugs in preventing neurodegeneration. We have also identified molecular events such as neuron cell cycle reentry and glial cell innate immune response activation that cause neurodegeneration, making these events high priority targets for drug therapy. Flies are well-suited for identifying drugs that are effective in the multicellular context of whole animals. The small size and short lifespan of flies make it possible to carry out screens of thousands of drugs. Drugs can be placed in fly food, flies eat the food, and neurodegeneration can be measured at points throughout the fly lifespan. In addition, although many aspects of fly and human development and physiology are quite different, the underlying molecular details are often very similar. So, drugs that are effective in flies have a reasonable probability of being effective in humans. To achieve the goal of identifying drugs that prevent neurodegeneration in A-T, we propose to screen 2,320 bioactive drugs for the ability to suppress the rough eye phenotype caused by ATM knockdown in the eye and the developmental lethality phenotype caused by an endogenous ATM mutation.

描述（由申请人提供）：我们建议确定预防人类疾病共济失调-毛细血管扩张症（A-T）神经退行性疾病的药物。A-T是一种罕见的遗传性疾病，其特征是共济失调，缺乏运动协调。小脑中的神经退行性事件导致共济失调开始于两岁之前，并随着年龄的增长而恶化，导致8至12岁之间的轮椅依赖。1995年，当缺陷基因A-T突变（ATM）被发现时，对神经变性原因的研究开始认真起来。然而，尽管在理解正常细胞中的ATM功能和ATM突变细胞中失调的细胞过程方面取得了相当大的进展，但还没有开发出预防神经变性的疗法。治疗发展的一个主要障碍是缺乏经历神经变性的A-T动物模型。我们已经建立了果蝇（Drosophila melanogaster）的A-T模型。果蝇模型概括了A-T患者中发生的进行性神经变性。使用这些模型，我们已经开发出可以用于测量药物在预防神经退行性变方面的有效性的测定方法。我们还确定了导致神经变性的分子事件，如神经元细胞周期重入和神经胶质细胞先天免疫应答激活，使这些事件成为药物治疗的高优先级靶点。苍蝇很适合用来鉴别 在整个动物的多细胞环境中有效。苍蝇体型小寿命短 使我们有可能对数千种药物进行筛选。药物可以放在苍蝇的食物中，苍蝇吃食物，神经退化可以在整个苍蝇生命周期的各个点进行测量。此外，虽然苍蝇和人类发育和生理的许多方面都有很大的不同，但潜在的分子细节往往非常相似。所以，有效的药物 苍蝇对人类有效的可能性是合理的。为了实现鉴定预防A-T神经变性的药物的目标，我们建议筛选2，320种生物活性药物，以抑制由眼内ATM敲低引起的粗糙眼表型和由内源性ATM突变引起的发育致死表型。