Neurodegeneration with Drosophila

果蝇神经变性

• 批准号: 6612622
• 负责人: Juan Botas
• 金额: $ 44.83万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6612622
• 关键词: Drosophilidae; Huntington's disease; arthropod genetics; cerebellar ataxia /dyskinesia; disease /disorder model; gene mutation; genetically modified animals; glutamine; homopeptide; nerve /myelin protein; neurotoxicology; neurotoxins; plasmids

DESCRIPTION (Adapted from applicant's abstract): The ultimate goal of this project is to gain insight into polyglutamine-induced neurodegeneration by identifying genes, pathways and molecular mechanisms involved in the pathogenesis of spinocerebellar ataxia type 1 (SCA1). A Drosophila model of SCA1 was created by generating flies that express either normal or expanded human SCA1 transgenes. This fly model recapitulates the cellular phenotypes observed in SCA1 patients including the formation of nuclear inclusions (NI) and progressive neuronal degeneration. Capitalizing on the power of Drosophila genetics, two large genetic screens were designed to identify genes that modify a SCA1 neurodegenerative phenotype in the eye. The first screen yielded modifiers of the SCA1 phenotype when gene activity was decreased; the second screen yielded SCA1 modifiers when gene activity was increased. Both suppressors and enhancers of the neurodegenerative phenotype were obtained from each screen. The first aim of the proposed work is to identify the genes that modify the SCA1 neurodegenerative phenotype. These modifiers will be further characterized in sensitive viability and locomoter assays that allow the quantification of their modifier effects. The most powerful suppressors will be selected for further studies. To investigate whether different polyglutamine disease share common mechanisms of pathogenesis, the SCA1 modifiers will be tested in fly models of Huntington disease and polyglutamine toxicity. Finally, because the normal function of the SCA1 gene may be relevant to pathogenesis, the function of the Drosophila SCA1 gene will be investigated by generating lack-of-function mutations and transgenes for its over expression. In future studies, the most promising SCA1 suppressors characterized in flies will be investigated in the SCA1 mouse model, and in mouse models of polyglutamine disease. These genes may also be relevant to research aimed at treating other neurodegenerative proteinopathies such as Alzheimer disease and Parkinson disease. They will provide valuable targets for future pharmacological research aimed at developing drugs for therapy.

描述（改编自申请人的摘要）：最终目标 项目是为了深入了解通过 识别参与的基因，途径和分子机制 1型脊椎子宫共济失调的发病机理（SCA1）。果蝇模型 SCA1是通过生成表达正常或扩展的苍蝇来创建的 人类SCA1转基因。这种苍蝇模型概括了细胞表型 在SCA1患者中观察到，包括形成核夹杂物（Ni） 和进行性神经元变性。利用果蝇的力量 遗传学，设计了两个大遗传筛选，以识别改变的基因 眼睛中的SCA1神经退行性表型。第一个屏幕产生 当基因活性降低时，SCA1表型的修饰符；第二个 当基因活性增加时，筛选产生了SCA1修饰符。两个都 从神经退行性表型的抑制剂和增强子 每个屏幕。拟议工作的第一个目的是确定基因 修改SCA1神经退行性表型。这些修饰符将进一步 以敏感的生存能力和运动器分析为特征，允许 定量其修饰效果。最强大的抑制器将是 选择进行进一步研究。研究是否不同的多谷氨酰胺 疾病具有发病机理的共同机制，SCA1修饰符将是 在亨廷顿疾病和聚谷氨酸毒性的苍蝇模型中进行了测试。最后， 因为SCA1基因的正常功能可能与发病机理有关 果蝇Sca1基因的功能将通过产生研究 缺乏功能突变和转基因的过度表达。 在未来的研究中，最有希望的SCA1抑制剂以苍蝇为特征 将在SCA1鼠标模型和小鼠模型中进行研究 聚谷氨酰胺疾病。这些基因也可能与针对的研究有关 治疗其他神经退行性蛋白质病，例如阿尔茨海默氏病和 帕金森病。他们将为未来提供宝贵的目标 药理研究旨在开发治疗药物。