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: 7675947
• 负责人: PETER T LANSBURY
• 金额: $ 8.44万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7675947
• 关键词: Age; Biological Models; Cells; Class; Collaborations; Dietary Fats; Dietary Fatty Acid; Disease; Drosophila genus; Exhibits; Future; Laboratories; Laboratory Research; Libraries; Literature; Maintenance; Methodology; Methods; Modeling; Nerve Degeneration; Neuroblastoma; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Postdoctoral Fellow; Research; Research Personnel; Resources; Scientist; Students; Testing; Toxic effect; Training; Transgenic Organisms; Work; alpha synuclein; base; chemical genetics; drug discovery; drug testing; feeding; fly; member; parkin gene/protein; research study; synuclein; tool

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，可以用来测试数百个，也许在未来，数千个（如果候选人，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，因为可以鉴定出不知道参与帕金森神经变性的靶点。我们的第一次筛选，超过650种FDA批准的药物，发现了两类抑制帕金森病表型的药物。事实上，大多数（10/12）的抑制化合物;聚集在这两个 研究小组证实了果蝇作为药物测试模型的实用性。根据目前的文献，预计这两个类别都不会有活动。这一结果证明了该方法用于产生关于PD发病机制的新假设的能力。已证明每类药物的成员可保护哺乳动物神经母细胞瘤细胞免受α-突触核蛋白毒性，支持果蝇用于研究哺乳动物疾病的相关性。我们Udall中心的核心B部分将支持持续的药物测试和旨在探索膳食脂肪对PD影响的研究。此外，我们计划使 这种方法可用于其他Udall中心的研究人员，无论是执行特定的实验，还是培训自己的科学家。该核心将成为PD研究的独特资源。