Probing Neurodegeneration with Drosophila

用果蝇探测神经退行性变

基本信息

批准号：
8098002
负责人：
Juan Botas
金额：
$ 32.91万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2013-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): 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 protein- protein-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 validate the genetic interaction between Ataxin-2 and Ataxin-1 in a knock-in mouse SCA1 model. Since these extensive comparative studies are impractical with mammalian models, we will use Drosophila models for the majority of the analysis and mouse models for validation of key interactions. 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. PUBLIC HEALTH RELEVANCE: The work in this proposal is aimed towards revealing mechanisms of pathogenesis and identifying potential therapeutic targets in Spinocerebellar ataxias. These basic studies are a prerequisite to developing therapies for these neurodegenerative disorders for which there are no effective treatments.

描述（由申请人提供）：该项目的最终目标是确定脊髓小脑性共济失调（SCAs）常见的发病机制和潜在治疗靶点的分子机制。这些是约 30 种遗传异质性神经退行性疾病，它们具有共同的神经病理学和临床特征，例如小脑萎缩以及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，遗传性共济失调的蛋白质-蛋白质相互作用网络表明，许多引起共济失调的蛋白质共享相互作用的伙伴。其次，dAtaxin-2（负责 SCA2 的蛋白质的直系同源物）是 Ataxin-1[82Q] 在 SCA1 果蝇模型中诱导的神经毒性的主要修饰剂。总之，这些观察结果表明，除了相似的神经病理学和临床特征之外，SCAs 以及其他遗传性共济失调可能具有共同的发病机制。这一假设预测 SCA 具有共同的基因修饰因子和仍未知的潜在治疗靶点。检验这一假设需要对不同遗传性共济失调之间的遗传修饰和发病机制进行彻底比较。将采用遗传方法来鉴定由扩展的 Ataxin-1、Ataxin-2 和 Ataxin-7（负责 SCA1、SCA2 和 SCA7 的蛋白质）引起的神经毒性修饰剂。这里提出的工作将解决以下具体目标：1）研究dAtaxin-2功能部分丧失抑制Ataxin-1[82Q]诱导的神经变性的分子机制。 2) 筛选共济失调相互作用组中 Ataxin-1[82Q] 诱导的神经毒性的遗传修饰因子。 3) 在SCA2和SCA7果蝇模型中测试Ataxin-1[82Q]遗传修饰剂和共济失调相互作用组。 4) 在敲入小鼠SCA1模型中验证Ataxin-2和Ataxin-1之间的遗传相互作用。由于这些广泛的比较研究对于哺乳动物模型来说是不切实际的，因此我们将使用果蝇模型进行大部分分析，并使用小鼠模型来验证关键相互作用。这项工作确定的神经变性抑制因子可能直接指向特定的治疗靶点。这些基础研究是开发针对这些尚无有效治疗方法的神经退行性疾病的疗法的先决条件。公共卫生相关性：本提案的工作旨在揭示脊髓小脑性共济失调的发病机制并确定潜在的治疗靶点。这些基础研究是开发针对这些尚无有效治疗方法的神经退行性疾病的疗法的先决条件。