Facility for drug testing in alpha-syn transgenic drosophila & new models of PD

α-syn 转基因果蝇药物测试设施

• 批准号: 7009789
• 负责人: PETER T LANSBURY
• 金额: $ 8.57万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009789
• 关键词: Drosophilidae; Parkinson' s disease; biomedical facility; dietary lipid; disease /disorder model; drug screening /evaluation; genetically modified animals; model design /development

Drugs can modify the course of neurodegeneration in ct-synuclein transgenic Drosophila. We developed a method that can be used to test hundreds, and perhaps in the future, thousands (if candidates, allowing an unbiased approach to be taken. This approach has the advantage over the currently prevalent approach to drug discovery in that targets that are not known to be involved in Parkinsonian neurodegeneration can be identified. Our first screen, of over 650 FDA-approved drugs, turned up two classes of drugs that suppress the Parkinsonian phenotype. The fact that most (10/12) of the suppressor compound; clustered into these two groups confirms the utility of Drosophila as a model for drug testing. Neither of these classes was expected to have activity, based on the current literature. This result demonstrates the power of the method for generating new hypotheses concerning PD pathogenesis. Members of each drug class have been demonstrated to protect mammalian neuroblastoma cells against alpha-synuclein toxicity, supporting the relevance of Drosophila for studying mammalian disease. The core B component of our Udall Center will support continued drug testing and the addition of studies aimed at probing the influence of dietary fats on PD. In addition, we plan to make this methodology available to investigators in other Udall centers, both for the execution of specific experiments, and for the training of their own scientists. This core will be a unique resource for PD research.

药物可以改变 ct-突触核蛋白转基因果蝇的神经变性过程。我们开发了一种方法，可以用于测试数百个，甚至将来可能是数千个（如果是候选者），从而允许采取公正的方法。这种方法比目前流行的药物发现方法具有优势，因为目标不是我们对 650 多种 FDA 批准的药物进行了首次筛选，发现了两类抑制帕金森表型的药物。抑制剂化合物聚集在这两个中； 研究小组证实了果蝇作为药物测试模型的效用。根据目前的文献，预计这些类别都不会有活动。这一结果证明了该方法产生有关 PD 发病机制的新假设的能力。每类药物的成员均已被证明可以保护哺乳动物神经母细胞瘤细胞免受α-突触核蛋白毒性，支持果蝇在研究哺乳动物疾病方面的相关性。我们 Udall 中心的核心 B 部分将支持持续的药物测试和增加旨在探讨膳食脂肪对 PD 影响的研究。此外，我们计划制作 其他尤德尔中心的研究人员可以使用这种方法，既可以用于执行特定实验，也可以用于培训自己的科学家。该核心将成为 PD 研究的独特资源。