Genetic Analysis of Neurodegeneration in Drosophila

果蝇神经变性的遗传分析

• 批准号: 9018070
• 负责人: DAVID WASSARMAN
• 金额: $ 32.92万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9018070
• 关键词: Age; Alzheimer' s Disease; Animal Model; Ataxia Telangiectasia; Cause of Death; Cell Cycle; Cell Cycle Regulation; Cell Nucleus; Cleaved cell; Cognitive deficits; Data; Disease; Drosophila genus; Drosophila melanogaster; Event; Excision; Experimental Models; Gene Targeting; Genes; Genetic Transcription; Goals; Health; Homologous Gene; Human; Immune; Immune response; Individual; Mammals; Mediating; Mitotic Cell Cycle; Modeling; Molecular; Molecular Genetics; Mutate; Mutation; NF-kappa B; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Pathway interactions; Phosphorylation; Proteins; Publishing; Rare Diseases; Research; Role; Signal Transduction; Stimulus; TNF gene; antimicrobial peptide; fly; gain of function; genetic analysis; human disease; loss of function; mutant; neuron loss; novel; pathogen; prevent; protein function; targeted treatment; tool; transcription factor

DESCRIPTION (provided by applicant): Neurodegeneration is characterized by the progressive loss of neuron function resulting in physical and cognitive defects that can cause death. Neurodegenerative diseases such as Alzheimer's are a substantial health issue. Currently, there is no effective means to prevent neurodegeneration in any disease. We want to understand the molecular and cellular events that are required for neurodegeneration in a rare disease Ataxia-telangiectasia (A-T), which is caused by mutation of the A- T mutated (ATM) gene. In A-T, neurodegeneration begins before the age of two and worsens with age. We have used Drosophila melanogaster as an experimental model to study A-T. To date, we have found that ATM mutations in neurons disrupt cell cycle regulation, which causes quiescent neurons to reenter the mitotic cell cycle and die. We have also found that ATM mutations in glial cells activate the innate immune response through the NF-¿B transcription factor Relish, which causes neurons to die. These findings in flies are relevant to humans. Neuron cell cycle reentry and activation of the innate immune response occur in individuals with A-T as well as in individuals with other neurodegenerative diseases such as Alzheimer's. In the proposed studies, we will continue to use flies because they are the only animal model currently available that undergoes neurodegeneration as a result of ATM mutation. Moreover, the arsenal of molecular and genetic tools available in flies make it possible to rapidly investigate the molecules and pathways that underlie neurodegeneration, providing a framework for developing targeted therapies. To delineate the pathway of events that cause neurodegeneration in A-T we proposed to: (1) determine the factors and signaling events that activate Relish to cause neurodegeneration in ATM mutant flies and (2) determine the transcription targets of Relish at are necessary and sufficient to cause neurodegeneration in ATM mutant flies.

描述（由申请人提供）：神经变性的特征是神经元功能的逐渐丧失，导致身体和认知缺陷，可导致死亡。像阿尔茨海默氏症这样的神经退行性疾病是一个严重的健康问题。目前，还没有有效的方法来预防任何疾病的神经退行性变。我们想了解由a- T突变（ATM）基因突变引起的罕见疾病共济失调毛细血管扩张（a- T）的神经退行性变所需的分子和细胞事件。在A-T中，神经变性在两岁之前就开始了，并随着年龄的增长而恶化。我们以黑腹果蝇作为实验模型来研究A-T。迄今为止，我们已经发现神经元中的ATM突变破坏细胞周期调节，导致静止神经元重新进入有丝分裂细胞周期并死亡。我们还发现，神经胶质细胞中的ATM突变通过NF-¿B转录因子激活先天免疫反应，导致神经元死亡。这些在苍蝇身上的发现也适用于人类。神经元细胞周期的重新进入和先天免疫反应的激活发生在患有A-T的个体以及患有其他神经退行性疾病（如阿尔茨海默氏症）的个体中。在拟议的研究中，我们将继续使用苍蝇，因为它们是目前唯一可用的由于ATM突变而经历神经变性的动物模型。此外，在果蝇中可用的分子和遗传工具使快速研究神经变性的分子和途径成为可能，为开发靶向治疗提供了框架。为了描述A-T中引起神经退行性变的事件通路，我们提出：(1)确定在ATM突变体果蝇中激活津津子导致神经退行性变的因素和信号事件；(2)确定津津子在ATM突变体果蝇中引起神经退行性变的必要和充分的转录靶点。