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识别发病机理和潜在治疗靶标的分子机制，这些靶标（SCAS）常见。这些是〜30组遗传异质性神经退行性疾病，具有神经病理和临床特征，例如小脑萎缩以及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，用于遗传性（遗传性（遗传性）的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伴侣。其次，dataxin-2（负责SCA2的蛋白质的直系同源物）是actaxin-1 [82q]诱导的SCA1模型中神经毒性的主要修饰剂。总之，这些观察结果表明，除了类似的神经病理学和临床特征外，SCAS以及其他遗传性共济失调可能还具有发病机理的分子机制。该假设预测，SCA具有常见的遗传修饰剂和潜在的治疗靶标，这些靶标仍然未知。检验该假设需要对不同遗传性共济失调之间的遗传修饰剂和发病机理的机制进行详尽的比较。将采用一种遗传方法来识别由Ataxin-1，ataxin-2和ataxin-7（负责SCA1，SCA2 A sca7）扩展引起的神经毒性的修饰剂。此处提出的工作将解决以下特定目的：1）研究分子机制，通过这种机制，dataxin-2函数抑制ataxin-1 [82q]诱导的神经变性的方法。 2）筛选共济失调相互作用的遗传改性剂[82q]诱导的神经毒性。 3）在SCA2和SCA7的果蝇模型中测试ataxin-1 [82q]遗传修饰剂和共济失调相互作用。 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与哺乳动物模型不切实际，因此我们将使用果蝇模型进行大多数分析和小鼠模型来验证关键相互作用。由于这项工作而识别的神经变性的抑制剂可能直接指向特定的治疗靶标。这些基础研究是开发这些神经退行性疾病的疗法的先决条件，这些疾病没有有效的治疗方法。公共卫生相关性：该提案中的工作旨在揭示发病机理的机制，并确定脊椎小脑共济失调中潜在的治疗靶标。这些基础研究是开发这些神经退行性疾病的疗法的先决条件，这些疾病没有有效的治疗方法。