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base; cell type; comparative; neuropathology; neurotoxicity; novel; protein protein interaction; therapeutic target; unpublished works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其分子机制 脊髓小脑常见的发病机制和潜在的治疗靶点 共济失调（SCAs）。这些是一组约 30 种具有遗传异质性的神经退行性疾病 具有共同神经病理学和临床特征的疾病，例如神经萎缩 小脑和运动协调和平衡丧失。 最近的数据表明遗传性共济失调之间存在意想不到的联系。首先，蛋白质蛋白质- 遗传性共济失调的相互作用网络揭示了许多引起共济失调的因素 蛋白质共享相互作用的伙伴。其次，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调节剂 SCA1的果蝇模型。总之，这些观察结果表明 SCA 和 也许其他遗传性共济失调可能具有相同的发病机制 除了相似的神经病理学和临床特征。这个假设预测 SCA 具有共同的基因修饰因子和潜在的治疗靶点 未知。检验这一假设需要对遗传修饰剂进行彻底比较 不同遗传性共济失调的发病机制及机制。 将采用遗传方法来识别引起的神经毒性的修饰因子 通过扩展 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标：1） 研究 dAtaxin-2 功能部分丧失的分子机制 抑制 Ataxin-1[82Q] 诱导的神经变性。 2）筛查共济失调 Ataxin-1[82Q] 诱导的神经毒性遗传修饰的相互作用组。 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组 SCA2 和 SCA7。 4) 研究选定的常见遗传修饰因子 果蝇 SCA 模型。 这些比较研究对于哺乳动物模型来说不切实际，但可行 使用果蝇。由此确定的神经变性抑制因子 工作可能直接指向特定的治疗目标。这些基础研究是 开发针对这些神经退行性疾病的疗法的先决条件 没有有效的治疗方法。