Zebrafish Assay for Parkinson's Disease Drugs

描述(申请人提供)：描述：该研究计划的目标是开发一种快速的体内试验，以筛选小分子保护或再生整个脊椎动物有机体中的神经元的能力。在第一阶段，斑马鱼胚胎中的多巴胺能神经元将暴露在神经毒素MPTP中，转基因斑马鱼胚胎中的多巴胺能神经元很容易被观察到。对神经元的损伤将根据神经元荧光的变化进行测量。已知功能的分子以及新的分子将被测试其保护神经元或促进神经元生长的能力，并以剂量依赖的方式进行。通过使用高含量荧光成像仪来量化96或384孔板格式的荧光变化，可以加速这一努力的成功，以允许在第二阶段进行更高的吞吐量筛查。该系统中识别的分子有可能成为治疗帕金森氏症等神经退行性疾病的新型药物。目前还没有任何治疗方法可以阻止帕金森氏症神经细胞死亡的进展，这增加了这一领域药物发现创新的必要性。由于目前利用细胞或外植体培养的高通量技术可能无法反映真实的体内环境，斑马鱼检测将代表着公共卫生研究化合物筛选方面的重大创新进展：本项目的目标是开发一种荧光斑马鱼检测方法，以监测神经毒素对神经元的损伤。保护神经元免受损伤的药物可能对帕金森氏症的治疗有用。

DESCRIPTION (provided by applicant): Description: The goal of this research program is to develop a rapid, in vivo assay for screening small molecules for their ability to protect or regenerate neurons in a whole vertebrate organism. In Phase I, dopaminergic neurons in zebrafish embryos, made easily visible by transgenic incorporation of a fluorescent protein, will be exposed to the neurotoxin MPTP. Damage to neurons will be measured based on changes in fluorescence of the neurons. Molecules of known function, as well as novel molecules, will then be tested for their ability to protect neurons or promote neuronal growth in a dose-dependent fashion. Success in this endeavor can be accelerated to allow higher throughput screening in Phase II by using a high content fluorescent imager to quantify changes in fluorescence in a 96 or 384-well plate format. Molecules identified in this system have the potential to serve as novel drugs for the treatment of neurodegenerative diseases such as Parkinson's disease. No current treatments have been shown to prevent the progression of neuronal cell death in Parkinson's disease, increasing the need for innovation in drug discovery in this area. Since current high throughput technologies which utilize cells or explants in culture may not reflect the true in vivo environment, the zebrafish assay will represent a significant innovative advance in compound screening of research to public health: The goal of this project is develop a fluorescent zebrafish assay to monitor damage to neurons induced by neurotoxins. Drugs that protect neurons from damage may be useful for the treatment of Parkinson's disease.