Development of a Zebrafish PD Drug Discovery Platform

斑马鱼 PD 药物发现平台的开发

基本信息

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
项目类别：
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

项目摘要

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.

我们必须制定合理、系统的药物治疗方法发现治疗帕金森氏症和其他神经系统疾病。啮齿动物模型有对于这一过程至关重要，但它们可能不是最佳的起点。 LRRK2 G2019S等位基因是最常见的帕金森病突变及其相应的已经在多种生物体中开发了动物模型。虽然现有的模型很有价值，我们设计了斑马鱼 LRRK2 G2019S 系列，这是一个独特的加速 PD 治疗的有力起点。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研究、疾病的细胞和生理机制。然而，斑马鱼的真正力量推动PD研究的关键在于能够进行变革性的实验其他模型无法轻易完成。能够在 96 孔培养皿中培养幼虫并通过水引入测试化合物，可以实现小分子的高通量筛选使用行为读数的分子。可检测数以万计的化合物以确定潜在的治疗药物，然后可以进一步改进以简化治疗药物发现管道。我们的长期目标是进行这样的筛选来搜索使用斑马鱼帕金森病模型调节帕金森病相关行为的化合物。为了使这种方法有效，反映患者行为的行为必须首先在我们的 LRRK2 G2019S 突变体中得到证明。本研究的目的是检测斑马鱼 LRRK2 的 PD 相关行为和多巴胺能群体 G2019S突变体以确定该模型是否适合高吞吐量化学筛选。如果成功的话，这种方法将超越鉴定直接 LRRK2 抑制剂并能够分离以下化合物：影响其他过程以补偿 LRRK2 功能障碍。