Automated Screening System for Modifiers of Cardiac Output in Zebrafish

斑马鱼心输出量调节因素的自动筛选系统

• 批准号: 7689914
• 负责人: ANTHONY A Ferrante
• 金额: $ 37.37万
• 依托单位: PHYSICAL SCIENCES, INC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689914
• 关键词: Address; Adverse effects; Algorithms; Analysis of Variance; Animal Testing; Animals; Anterior; Aorta; Automation; Biological Assay; Blood; Blood flow; Caliber; Cardiac; Cardiac Output; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Collection; Computer software; Data; Data Collection; Detection; Development; Disease; Dorsal; EFRAC; Embryo; Evaluation; Fishes; Funding; Government; Heart; Heart Rate; Heart failure; Image; Laboratories; Larva; Lead; Length; Letters; Location; Maps; Measurement; Measures; Methods; Microscope; Modeling; Nature; Optical Coherence Tomography; Optics; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Positioning Attribute; Process; Protein Structure Initiative; Pulsatile Flow; Research; Research Design; Resolution; Scanning; Schedule; Screening procedure; Speed; Staging; Stroke Volume; System; Technology; Testing; Time; Toxic effect; Toxicology; United States National Institutes of Health; Ventricular; Ventricular End-Systolic Volumes; Zebrafish; base; clinically relevant; computerized data processing; data acquisition; design; drug discovery; drug testing; heart imaging; high throughput screening; human disease; image processing; improved; instrument; mutant; novel; physical science; programs; public health relevance; small molecule

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 both modifiers of normal cardiovascular processes and modifiers of cardiovascular disease. High-throughput systems under development aim to measure heart rate but do not address other critical parameters of cardiovascular function such as blood velocity, stroke volume and ejection fraction. We propose to develop a high-throughput system that would simultaneously: 1) measure heart rate; 2) generate a velocity profile of the ventral aorta; and 3) measure end diastolic and end systolic ventricular volume. The microscope-based system will utilize spectral domain optical coherence tomography with Doppler to generate, within a matter of seconds, a three dimensional structural image of zebrafish embryos and larvae and measure blood flow. In Phase I we developed a breadboard system that enabled collection of images from both the dorsal and ventral views of the animals. In the breadboard system the animals were located and the scan angle was adjusted manually. In Phase II a complete, automated screening system will be developed that includes: 1) software algorithms to rapidly locate the animals for imaging and adjust the scan angle along their axial length; 2) automated image collection; and 3) automated image processing. Phase II testing will include a pilot screen to detect animals with decreased cardiac output. PUBLIC HEALTH RELEVANCE: This research will develop technologies that will enable the use of zebrafish models of human disease in high-throughput screens for active pharmaceutical compounds. In particular, such screens are expected to accelerate discovery of new pharmaceuticals to treat cardiovascular diseases. These technologies will also enable high-throughput assays of cardiotoxicity.

描述（由申请人提供）：斑马鱼（Danio rerio）已被广泛接受为人类疾病的模型。已经进行小分子筛选来鉴定正常心血管过程的调节剂和心血管疾病的调节剂。正在开发的高通量系统旨在测量心率，但不涉及心血管功能的其他关键参数，例如血流速度、每搏输出量和射血分数。我们建议开发一种高通量系统，该系统可以同时：1）测量心率； 2) 生成腹主动脉的速度分布图； 3) 测量舒张末期和收缩末期心室容积。基于显微镜的系统将利用多普勒谱域光学相干断层扫描在几秒钟内生成斑马鱼胚胎和幼虫的三维结构图像并测量血流。在第一阶段，我们开发了一个面包板系统，可以收集动物的背侧和腹侧视图的图像。在面包板系统中定位动物并手动调整扫描角度。在第二阶段，将开发一个完整的自动筛选系统，包括：1）软件算法，用于快速定位动物进行成像并沿其轴向长度调整扫描角度； 2）自动化图像采集； 3）自动图像处理。第二阶段测试将包括一个试点筛选，以检测心输出量减少的动物。公共健康相关性：这项研究将开发能够在活性药物化合物的高通量筛选中使用人类疾病斑马鱼模型的技术。特别是，此类筛选有望加速治疗心血管疾病的新药物的发现。这些技术还将实现心脏毒性的高通量测定。