Probing Neurodegeneration with Drosophila

用果蝇探测神经退行性变

• 批准号: 7625349
• 负责人: Juan Botas
• 金额: $ 38.38万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625349
• 关键词: Address; Ataxia; Atrophic; Behavioral; Biological Assay; Cerebellum; Characteristics; Clinical; Comparative Study; Data; Disease; Drosophila genus; Elements; Equilibrium; Eye; Genetic; Genetic Screening; Genome; Goals; Inherited; LY6E gene; Link; Modeling; Molecular; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neuromuscular Diseases; Pathogenesis; Pathology; Peripheral Nervous System; Phenotype; Proteins; Publishing; SCA2 protein; SCA7 protein; Sensory; Spinocerebellar Ataxias; Testing; Type 1 Spinocerebellar Ataxia; Validation; Work; ataxin-1; base; cell type; comparative; neuropathology; neurotoxicity; novel; protein protein interaction; therapeutic target; unpublished works

The ultimate goal of this project is to identify molecular mechanisms of pathogenesis and potential therapeutic targets that are common to Spinocerebellar ataxias (SCAs). These are a group ~30 genetically heterogeneous neurodegenerative disorders that share neuropathological and clinical features such as atrophy of the cerebellum and loss of motor coordination and balance. Recent data points to unsuspected links among inherited ataxias. First, a proteinprotein- interaction network for inherited ataxias revealed that many ataxia-causing proteins share interacting partners. Second, dAtaxin-2 (an orthologue of the protein responsible for SCA2) is a major modifier of Ataxin-1[82Q]-induced neurotoxicity in a Drosophila model of SCA1. Together, these observations suggest that SCAs, and perhaps other inherited ataxias may share molecular mechanisms of pathogenesis in addition to similar neuropathology and clinical features. This hypothesis predicts that SCAs have common genetic modifiers and potential therapeutic targets that remain unknown. Testing this hypothesis requires a thorough comparison of genetic modifiers and mechanisms of pathogenesis among different inherited ataxias. A genetic approach will be employed to identify modifiers of neurotoxicity caused by expanded Ataxin-1, Ataxin-2 and Ataxin-7, the proteins responsible for SCA1, SCA2 an SCA7. The work proposed here will address the following specific aims: 1) To investigate the molecular mechanisms by which partial loss of dAtaxin-2 function suppresses Ataxin-1[82Q]-induced neurodegeneration. 2) To screen the ataxia interactome for genetic modifiers of Ataxin-1[82Q]-induced neurotoxicity. 3) To test the Ataxin-1[82Q] genetic modifiers and the ataxia interactome in Drosophila models of SCA2 and SCA7. 4) To investigate selected genetic modifiers that are common to the Drosophila SCA models. These comparative studies are impractical with mammalian models, but feasible using Drosophila. The suppressors of neurodegeneration identified as a result of this work may directly point to specific therapeutic targets. These basic studies are prerequisite to developing therapies for these neurodegenerative disorders for which there are no effective treatments.

该项目的最终目标是确定分子机制 发病机理和潜在的治疗靶标的脊髓杆菌 共济失调（SCAS）。这些是〜30的基因神经退行性的30组 具有神经病理学和临床特征的疾病，例如 小脑和运动协调和平衡的丧失。 最近的数据指出了遗传性（遗传性（遗传性）的链接之间的链接。首先，蛋白质蛋白 - 遗传性共济失调的相互作用网络表明许多引起共济失调的原因 蛋白质共享互动伙伴。第二，Dataxin-2（蛋白质的直系同源物 负责SCA2）是Ataxin-1 [82Q]诱导的神经毒性的主要修饰符 SCA1的果蝇模型。这些观察结果一起表明SCA和 也许其他遗传性共济失调可能会共享发病机理的分子机制 除了类似的神经病理学和临床特征。该假设预测 SCA具有常见的遗传修饰剂和潜在的治疗靶标的 未知。检验该假设需要对遗传修饰符进行详尽的比较 以及不同遗传性共济失调之间发病机理的机制。 将采用一种遗传方法来识别引起的神经毒性的修饰符 通过扩展的ataxin-1，ataxin-2和ataxin-7，负责SCA1，SCA2的蛋白质 SCA7。这里提出的工作将解决以下具体目的：1） 研究dataxin-2功能部分损失的分子机制 抑制ataxin-1 [82q]诱导的神经变性。 2）筛选共济失调 相互作用组，用于共生1的遗传修饰剂[82Q]诱导的神经毒性。 3）测试 ataxin-1 [82q]遗传修饰剂和果蝇模型中的共济失调相互作用 SCA2和SCA7。 4）研究选定的遗传修饰符 果蝇SCA模型。 这些比较研究与哺乳动物模型不切实际，但可行 使用果蝇。识别为此的神经变性的抑制剂 工作可能直接指向特定的治疗靶标。这些基础研究是 为这些神经退行性疾病开发疗法的先决条件 没有有效的治疗方法。