Neuroprotective drugs for A-T

描述（由申请人提供）：我们建议鉴定预防人类疾病共济失调-毛细血管扩张（A-T）神经变性的药物。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。导致共济失调的小脑神经退行性事件在两岁之前就开始了，随着年龄的增长而恶化，导致8到12岁之间依赖轮椅。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正式开始。然而，尽管在了解ATM在正常细胞中的功能和ATM突变细胞中失调的细胞过程方面取得了相当大的进展，但尚未开发出预防神经变性的治疗方法。发展治疗的一个主要障碍是缺乏经历神经变性的A- t动物模型。我们已经创造了果蝇（Drosophila melanogaster）的A-T模型。苍蝇模型概括了在A-T患者中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变性方面的有效性的检测方法。我们还发现了导致神经变性的分子事件，如神经元细胞周期再进入和神经胶质细胞先天免疫反应激活，使这些事件成为药物治疗的优先目标。苍蝇很适合识别药物

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.