Neuroprotective drugs for A-T

A-T 神经保护药物

基本信息

批准号：
8739687
负责人：
DAVID WASSARMAN
金额：
$ 18.22万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2015-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8739687
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

项目摘要

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）：我们建议鉴定可预防人类疾病性共济失调性链血管症（A-T）中神经退行性的药物。 A-T是一种罕见的遗传疾病，其特征是共济失调，缺乏运动配位。小脑中产生共济失调的神经退行性事件在两岁之前开始，随着年龄的增长而变得更糟，导致轮椅依赖在八至十二岁之间。对神经退行性原因的研究始于1995年，当时发现有缺陷的基因A-T突变（ATM）。然而，尽管在理解正常细胞和ATM突变细胞中失调的正常细胞过程中的ATM功能方面取得了很大进展，但尚未开发出可预防神经变性的疗法。疗法发展的主要障碍是缺乏经历神经变性的A-T动物模型。我们创建了A-T的果蝇（果蝇Melanogaster）模型。飞行模型概括了在A-T患者中发生的进行性神经变性。使用这些模型，我们开发了可以用来衡量药物在预防神经变性的有效性的测定。我们还鉴定了分子事件，例如神经元细胞周期再入和神经胶质细胞的免疫反应激活，引起神经变性，从而使这些事件具有很高的优先级药物治疗靶标。苍蝇非常适合识别的药物在整个动物的多细胞环境中有效。小尺寸和苍蝇的寿命短使得可以执行数千种药物的屏幕。可以将药物放在飞蝇中，果蝇吃食物，并且可以在整个飞行寿命的点上测量神经退行性。此外，尽管苍蝇，人类发育和生理学的许多方面截然不同，但基本的分子细节通常非常相似。因此，有效的药物苍蝇具有在人类中有效的合理可能性。为了实现鉴定预防A-T中神经退行性的药物的目标，我们建议筛选2,320名生物活性药物，以抑制眼睛中AMT敲低和由内源性ATM引起的发育致死表型引起的粗糙眼表型的能力。