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Fully automated angiogenesis drug discovery assay in Zebrafish

斑马鱼全自动血管生成药物发现测定

基本信息

批准号：
7745544
负责人：
ANTHONY A Ferrante
金额：
$ 19.99万
依托单位：
PHYSICAL SCIENCES, INC
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7745544
关键词：
9-deoxy-delta-9-prostaglandin D2 Agonist Algorithms Angiogenesis Promoter Animals Aorta Automation Biological Assay Bladder Blood Vessels Brightfield Microscopy Cells Chemicals Collection Computer software Contracts Data Collection Data Set Detection Dimensions Disease Doctor of Philosophy Dorsal Embryo Ensure Evaluation Research Eye Fishes Fluorescence Genetic Government Green Fluorescent Proteins Heart Image Image Analysis Imagery Laboratories Laboratory Study Larva Lateral Length Lighting Location Macular degeneration Malignant Neoplasms Manuals Maps Masks Measurement Methods Microscope Modeling Modification Nanotechnology Normal Range Pattern Pediatrics Peroxisome Proliferators Persons Phase Phase II Clinical Trials Probability Process Receptor Signaling Reporting Resolution Rotation SIV Side Source Staging Structure Structure of posterior cardinal vein Swimming Testing Therapeutic Time Tissues Training Transgenic Organisms Vascular Endothelial Growth Factors Veins Wisconsin Work Zebrafish angiogenesis assay development base drug development drug discovery falls fluorescence imaging high throughput screening human disease image processing in vivo instrumentation interest medical schools new growth novel physical science prevent professor programs protein expression public health relevance receptor small molecule software development success tool troglitazone

项目摘要

DESCRIPTION (provided by applicant): The zebrafish, Danio rerio, has become widely accepted as a model for human disease. Small molecule screens have been performed to identify modifiers of vascular patterning but this process has been performed at relatively low throughput since the tools for fully automated processing are not yet available. We propose to develop a novel, high-throughput screening assay for angiogenesis promoters. The assay would be based on the use of the SideView" microplate to collect clear images of the vascular pattern in animals that express GFP in their vasculature. Specifically, during Phase I we propose to: 1) develop novel methods to modulate angiogenesis promoters in the subintestinal veins; 2) develop software that will locate the zebrafish, identify the region of interest, move that region to the center of the field of view, zoom in and refocus on the SIVs, and collect the image; and 3) develop automated, post-acquisition image processing software that will identify animals in which the extent of budding from the SIV is either enhanced or reduced. Methods for automated handling of the animals will also be developed during Phase I. During Phase II the methods, software and instrumentation will be fully integrated and a high-throughput screen for angiogenic compounds 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 either: promote growth of new blood vessels to prevent or reverse damage to heart tissue; or to inhibit growth of new blood vessels as a treatment for numerous diseases including cancer and wet macular degeneration. 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)：斑马鱼，Danio rerio，已被广泛接受为人类疾病的模型。已经进行了小分子筛选来识别血管图案的修饰剂，但由于用于全自动处理的工具尚不可用，该过程以相对较低的吞吐量进行。我们建议开发一种新的、高通量的血管生成促进剂的筛选方法。该分析将基于SideView“微板”的使用，以收集在其血管系统中表达GFP的动物的血管图案的清晰图像。具体地说，在第一阶段，我们建议：1)开发新的方法来调节肠道下静脉中的血管生成启动子；2)开发软件，以定位斑马鱼，识别感兴趣的区域，将该区域移动到视野中心，放大并重新聚焦SIV，并收集图像；以及3)开发自动化的采集后图像处理软件，该软件将识别SIV萌芽的程度被增强或降低的动物。在第一阶段，还将开发自动处理动物的方法。在第二阶段，这些方法、软件和仪器将完全集成，并将对血管生成化合物进行高通量筛选。与公众健康相关：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，这些化合物可以：促进新血管的生长，以防止或逆转对心脏组织的损害；或抑制新血管的生长，用于治疗包括癌症和湿性黄斑变性在内的多种疾病。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。