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共济失调毛细血管扩张症（A-T）中神经变性的药物。 A-T 是一种罕见的遗传性疾病，其特征是共济失调，缺乏运动协调性。导致共济失调的小脑神经退行性事件在两岁之前就开始出现，并随着年龄的增长而恶化，导致八岁至十二岁之间对轮椅的依赖。 1995 年，当缺陷基因 A-T 突变 (ATM) 被发现时，人们开始认真研究神经退行性疾病的原因。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，但尚未开发出预防神经退行性变的疗法。治疗方法开发的一个主要障碍是缺乏发生神经变性的 A-T 动物模型。我们创建了 A-T 果蝇（Drosophila melanogaster）模型。果蝇模型再现了 A-T 患者中发生的进行性神经变性。利用这些模型，我们开发了可用于测量药物预防神经退行性变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，例如神经元细胞周期折返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。苍蝇非常适合识别以下药物：在整个动物的多细胞环境中有效。苍蝇体型小，寿命短使得对数千种药物进行筛选成为可能。可以将药物放入苍蝇食物中，苍蝇吃掉食物，并且可以在苍蝇整个生命周期的各个时间点测量神经退行性变。此外，尽管果蝇和人类发育和生理学的许多方面有很大不同，但潜在的分子细节往往非常相似。那么，有效的药物苍蝇有可能对人类有效。为了实现识别预防 A-T 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，以确定它们是否能够抑制因 ATM 敲低引起的眼部粗糙表型以及因内源性 ATM 突变引起的发育致死表型。