Development of a Zebrafish PD Drug Discovery Platform

斑马鱼 PD 药物发现平台的开发

• 批准号: 9372289
• 负责人: HOWARD I SIROTKIN
• 金额: $ 7.7万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9372289
• 关键词: Acoustics; Alleles; Animal Model; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain imaging; Chemicals; Clinical; Clinical Trials; Development; Disease; Disease model; Engineering; Environmental Risk Factor; Etiology; Frequencies; Functional disorder; Gene Targeting; Genetic; Goals; Human; Immunohistochemistry; Invertebrates; LRRK2 gene; Larva; Lesion; Leucine-Rich Repeat; Light; Link; Methods; Midbrain structure; Modeling; Molecular; Movement; Musculoskeletal Equilibrium; Mutation; Neurodegenerative Disorders; Organism; Parkinson Disease; Parkinsonian Disorders; Patients; Phenotype; Phosphotransferases; Physiological; Population; Preclinical Drug Evaluation; Process; Reporter; Research; Resolution; Rodent Model; Speed; Stimulus; Substantia nigra structure; Testing; Therapeutic; Therapeutic Agents; Transgenic Organisms; United States; Validation; Water; Zebrafish; base; dopaminergic neuron; drug discovery; experimental study; flexibility; gain of function; high throughput screening; kinase inhibitor; motor impairment; mutant; nervous system disorder; neuron loss; response; small molecule; stem

It is imperative that we develop rational and systematic approaches to drug discovery to treat Parkinson's and other neurological disorders. Rodent models are essential to this process, but they may not be the optimal starting place. The LRRK2 G2019S allele is the most common Parkinson's disease mutation and corresponding animal models have been developed in a variety of organisms. While the existing models are valuable, we engineered a zebrafish LRRK2 G2019S line that is a uniquely powerful starting place to accelerate PD therapeutics. The experimental flexibility of zebrafish including rapid gene targeting and unparalleled high-resolution functional brain imaging empowers studies of molecular, cellular and physiological mechanism of disease. However, the true power of zebrafish to promote PD research lies in the ability to conduct transformative experiments that cannot readily be done with other models. The ability to culture larvae in 96-well dishes and introduce test compounds via the water enables high throughput screening of small molecules using behavioral readouts. Tens of thousands of compounds can be assayed to identify potential therapeutic agents that can then be further refined to streamline the drug discovery pipeline. Our long-term goal is to perform such a screen to search for compounds that modulate Parkinsonian related behaviors using a zebrafish PD model. In order for this approach to be effective, behaviors that reflect those in patients must first be demonstrated in our LRRK2 G2019S mutant. The objectives of this study are to assay PD-related behaviors and dopaminergic populations in the zebrafish LRRK2 G2019S mutants to determine whether this model is a suitable substrate for high throughput chemical screens. If successful, this approach would go beyond identification of direct LRRK2 inhibitors and enable isolation of compounds that influence other processes to compensate for LRRK2 dysfunction.

我们必须开发理性和系统的药物方法 发现治疗帕金森氏症和其他神经系统疾病的发现。啮齿动物模型是 对于此过程至关重要，但它们可能不是最佳起点。 LRRK2 G2019S等位基因是最常见的帕金森氏病突变和相应的 动物模型已在各种生物体中开发。而存在 型号很有价值，我们设计了斑马鱼LRRK2 G2019S系列，这是一条独特的 强大的起点可以加速PD治疗疗法。 斑马鱼的实验灵活性，包括快速基因靶向和 无与伦比的高分辨率功能性脑成像使分子的研究能力， 疾病的细胞和生理机制。但是，斑马鱼的真正力量 促进PD研究在于能够进行变革性实验的能力 不能轻易地使用其他型号完成。在96孔菜肴中培养幼虫的能力 并通过水引入测试化合物，可实现小的吞吐量筛选 分子使用行为读数。可以分析成千上万种化合物 识别潜在的治疗剂，然后可以进一步完善以简化 药物发现管道。我们的长期目标是执行这样的屏幕以搜索 使用斑马鱼PD模型调节帕金森氏症相关行为的化合物。 为了使这种方法有效，反映患者中的行为必须 首先在我们的LRRK2 G2019S突变体中得到证明。这项研究的目标是 斑马鱼LRRK2中的测定与PD相关的行为和多巴胺能种群 G2019S突变体确定此模型是否是适合高的底物 吞吐量化学屏幕。如果成功，这种方法将超越 鉴定直接LRRK2抑制剂，并能够隔离化合物 影响其他过程以补偿LRRK2功能障碍。