Neuroprotective drugs for A-T

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)神经退行性变的药物。A-T是一种罕见的遗传性疾病，其特征是共济失调，即缺乏运动协调。导致共济失调的小脑神经变性事件在两岁之前就开始出现，并随着年龄的增长而恶化，导致8岁至12岁之间对轮椅的依赖。对神经退行性变原因的研究始于1995年，当时发现了有缺陷的基因A-T突变(ATM)。然而，尽管在理解ATM在正常细胞中的功能和在ATM突变细胞中调节失调的细胞过程方面取得了相当大的进展，但还没有开发出防止神经退化的治疗方法。开发治疗方法的一个主要障碍是缺乏经历神经退化的A-T动物模型。我们已经创造了A-T的果蝇(Drophila Blackogaster)模型。苍蝇模型概括了A-T患者发生的进行性神经变性。利用这些模型，我们开发了可以用来衡量药物在预防神经退行性变方面的有效性的分析方法。我们还确定了导致神经变性的分子事件，如神经细胞周期重入和神经胶质细胞天然免疫反应激活，使这些事件成为药物治疗的高优先靶点。苍蝇非常适合识别那些 在整个动物的多细胞环境中有效。苍蝇体型小、寿命短 使对数千种药物进行筛选成为可能。药物可以放在苍蝇的食物中，苍蝇吃食物，神经退化可以在苍蝇整个生命周期的某个时间点进行测量。此外，尽管苍蝇和人类的发育和生理在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，有效治疗的药物 苍蝇对人类有效的可能性是合理的。为了实现识别预防A-T中神经退行性变的药物的目标，我们建议筛选2,320种生物活性药物来抑制由眼内ATM基因敲除引起的粗糙眼表型和由内源性ATM突变引起的发育致死性表型。

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.