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High Content Discovery Assay for Muscular Dystrophy Therapeutics

肌营养不良疗法的高内涵发现测定

基本信息

批准号：
7802041
负责人：
ANTHONY A Ferrante
金额：
$ 19.84万
依托单位：
PHYSICAL SCIENCES, INC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7802041
关键词：
Address Affect Anesthetics Animals Biological Assay Birefringence Canis familiaris Cessation of life Collaborations Collection Computer software Connective Tissue Contracts Cycloparaffins Data Defect Deglutition Dependence Deterioration Development Disease Disease model Dystrophin Ethics Evaluation Exhibits Fatty acid glycerol esters Fertilization Fiber Film Functional disorder Funding Genes Glass Government Hereditary Disease Human Image Image Analysis Injection of therapeutic agent Larva Libraries Life Link Masks Measurement Measures Methods Modeling Molds Muscle Muscle Fibers Muscular Dystrophies Myopathy Necrosis Optics Organ Orthologous Gene Pattern Performance Persons Phase Phenotype Polarization Microscopy Probability Process Production Protein Structure Initiative Reagent Reporting Reproducibility Research Resolution Rest Rodent Screening procedure Side Signal Transduction Skeletal Development Skeletal Muscle Skin Stress Structure Surface Technology Testing Therapeutic Time Transcript United States National Institutes of Health Variant Vertebrates Wisconsin Zebrafish base computerized data processing copolymer cost disability drug development drug discovery effective therapy genome database human disease male medical schools model development mouse model muscle degeneration novel therapeutics physical science premature programs prototype public health relevance skeletal small molecule libraries success tool zebrafish genome

项目摘要

DESCRIPTION (provided by applicant): Muscular Dystrophy (MD) refers to a group of genetic disorders that cause progressive loss of strength in skeletal muscle leading to varying degrees of disability and, often, premature death. Duschenne's MD is both the most common and one of the most severe of these diseases affecting approximately 1 in 3,500 males and is caused by abnormalities in the gene encoding dystrophin. There are currently no specific treatments for MD. Discovery of novel therapeutics for MD is inhibited by a lack of adequate disease models that are amenable to either high-throughput or high-content screens. The zebrafish, Danio rerio, has become widely accepted as a model for human disease. It is genetically and anatomically similar to other vertebrates, and its external development and optical transparency greatly facilitate real time observation of its internal organs. Zebrafish models for a number of MDs have been developed and show great promise for chemical library screening. In Phase I, PSI plans to develop a high-content, moderate throughput, quantitative, image-based, drug discovery assay using zebrafish MD models in combination with PSI's SideView microplate technology. In Phase II: reagents and consumables will be validated and automated image analysis tools will be developed; and a compound library screen will be performed. PUBLIC HEALTH RELEVANCE: The Phase I and Phase II programs will develop a fully automated tool for discovery of potential therapeutic compounds that reverse the muscle damage caused by Muscular Dystrophy. The assay will be performed in zebrafish larvae which will result in a higher probability that identified compounds will proceed through the drug development process.

描述(申请人提供)：肌营养不良症(MD)是指一组遗传性疾病，导致骨骼肌力量进行性丧失，导致不同程度的残疾，通常还会过早死亡。Duschenne‘s MD是这些疾病中最常见也是最严重的疾病之一，大约每3500名男性中就有一人受到影响，由编码抗肌营养不良蛋白的基因异常引起。目前还没有针对MD的特效治疗方法。由于缺乏适用于高通量或高内容筛选的适当疾病模型，MD新疗法的发现受到阻碍。斑马鱼Danio Rerio已被广泛接受为人类疾病的模型。它在基因和解剖学上与其他脊椎动物相似，其外部发育和光学透明度极大地方便了对其内部器官的实时观察。针对一些MD的斑马鱼模型已经被开发出来，并显示出在化学文库筛选方面的巨大前景。在第一阶段，PSI计划利用斑马鱼MD模型与PSI的SideView微板技术相结合，开发一种高含量、中等吞吐量、定量、基于图像的药物发现试验。在第二阶段：将对试剂和消耗品进行验证，开发自动图像分析工具；并进行复合库筛选。公共卫生相关性：第一阶段和第二阶段计划将开发一种全自动工具，用于发现潜在的治疗化合物，逆转肌营养不良症造成的肌肉损伤。该检测将在斑马鱼幼体中进行，这将导致已确定的化合物在药物开发过程中进行的可能性更大。