Neurodegeneration with Drosophila

果蝇神经变性

• 批准号: 6769927
• 负责人: Juan Botas
• 金额: $ 33.86万
• 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/6769927
• 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）：本项目的最终目标 该项目的目的是通过以下方式深入了解多聚谷氨酰胺诱导的神经变性： 识别参与该过程的基因、途径和分子机制 脊髓小脑共济失调 1 型 (SCA1) 的发病机制。果蝇模型 SCA1 是通过生成表达正常或扩展的果蝇而创建的 人类 SCA1 转基因。该果蝇模型概括了细胞表型 在 SCA1 患者中观察到，包括核包涵体的形成 (NI) 和进行性神经元变性。利用果蝇的力量 在遗传学方面，设计了两个大型遗传筛选来识别修饰基因 眼部 SCA1 神经退行性表型。第一个屏幕产生了 当基因活性降低时 SCA1 表型的修饰因子；第二个 当基因活性增加时，筛选产生了 SCA1 修饰物。两个都 神经退行性表型的抑制子和增强子是从 每个屏幕。拟议工作的首要目标是确定基因 改变 SCA1 神经退行性表型。这些修改器将进一步 其特点是灵敏的活力和运动测定，允许 量化它们的修饰效果。最强大的抑制器将是 选择继续深造。研究不同的聚谷氨酰胺是否 疾病具有共同的发病机制，SCA1 修饰因子将是 在亨廷顿病和聚谷氨酰胺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有关， 果蝇 SCA1 基因的功能将通过生成 功能缺失突变和过度表达的转基因。 在未来的研究中，果蝇中最有前途的 SCA1 抑制剂 将在 SCA1 小鼠模型和 小鼠模型中进行研究 多聚谷氨酰胺病。这些基因也可能与旨在 治疗其他神经退行性蛋白质病，例如阿尔茨海默病和 帕金森病。他们将为未来提供有价值的目标 旨在开发治疗药物的药理学研究。