A TOXIN BASED DROSOPHILA PARKINSON'S DISEASE MODEL

基于毒素的果蝇帕金森病模型

• 批准号: 6882842
• 负责人: GEOFFREY E STILWELL
• 金额: $ 19.85万
• 依托单位: CAMBRIA BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882842
• 关键词: Drosophilidae; Parkinson' s disease; biomarker; disease /disorder model; dopamine; dosage; model design /development; neural degeneration; neurotoxicology; plant insecticide; technology /technique development

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is the second most common neurodegenerative disorder and afflicts approximately 1% of the population over 60. The etiology of PD remains elusive despite significant recent research advances, but both environmental and genetic factors are thought to contribute in the majority of cases of sporadic disease. Current existing PD models are either genetic, based on disease associated mutations in single loci, or toxicant-induced, based on a small handful of compounds that elicit symptoms and pathology similar to disease features in humans on physiological, cellular and molecular levels. Genetic and toxicant models of PD both implicate oxidative stress, protein folding defects and proteosome dysfunction as underlying causes of the disease; however, the specific relationships between the affected pathways in these different models remain largely unexplored. Furthermore, there is a dearth of information regarding how gene environment interactions contribute to disease pathogenesis. To begin to address these outstanding questions, we propose to develop a toxicant-based model of PD in the model organism Drosophila melanogaster. This in vivo model is based on our preliminary studies that have demonstrated acute toxicity and behavioral deficits in flies treated with the prototypical systemic complex I inhibitor compound, rotenone. Once operational, this model will take advantage of the extensive preexisting genetic and molecular tools available in flies, as well as the Drosophila genetic PD models in order to better characterize genetic contributions to environmental insults and pathways resulting in neurodegeneration. For this application, our specific aims are: (1) to characterize chronic, subacute dose-response profiles in flies treated with complex I inhibitor toxicant compounds, and (2) to characterize dopaminergic neuron loss induced by complex I toxicant administration by neuronal subtype-specific analysis. As a result of this project, our future plans and Phase II SBIR expectations include using this Drosophila toxicant-induced PD model for in vivo compound screening for therapeutic drug discovery and the identification of validated targets through genetic analysis of enhancers and suppressors.

描述（由申请人提供）：帕金森病 (PD) 是第二常见的神经退行性疾病，约 1% 的 60 岁以上人口受到影响。尽管最近的研究取得了重大进展，但帕金森病的病因仍然难以捉摸，但人们认为环境和遗传因素都与帕金森病有关有助于解决大多数散发性疾病的病例。目前现有的帕金森病模型要么是遗传性的，基于单个位点的疾病相关突变，要么是毒物诱导的，基于少数化合物，这些化合物在生理、细胞和分子水平上引发与人类疾病特征相似的症状和病理。 PD 的遗传和毒物模型均表明氧化应激、蛋白质折叠缺陷和蛋白酶体功能障碍是该疾病的根本原因；然而，这些不同模型中受影响途径之间的具体关系在很大程度上仍未得到探索。此外，关于基因环境相互作用如何影响疾病发病机制的信息也很缺乏。为了开始解决这些悬而未决的问题，我们建议在模式生物果蝇中开发一种基于毒物的帕金森病模型。该体内模型基于我们的初步研究，这些研究已证明用原型全身复合物 I 抑制剂化合物鱼藤酮治疗的果蝇会出现急性毒性和行为缺陷。一旦投入运行，该模型将利用果蝇中现有的广泛遗传和分子工具以及果蝇遗传 PD 模型，以便更好地表征遗传对环境损害和导致神经变性的途径的贡献。对于本应用，我们的具体目标是：(1) 表征用复合物 I 抑制剂毒物化合物处理的果蝇的慢性、亚急性剂量反应曲线，以及 (2) 表征由神经元亚型施用复合物 I 毒物引起的多巴胺能神经元损失。具体分析。作为该项目的结果，我们未来的计划和 II 期 SBIR 期望包括使用果蝇毒物诱导的 PD 模型进行体内化合物筛选，以发现治疗药物，并通过增强子和抑制子的遗传分析来鉴定经过验证的靶点。