High-speed opto-fluidics to screen entire nervous system in aging and disease

高速光流控技术可筛查整个神经系统的衰老和疾病

基本信息

批准号：
8181677
负责人：
ADELA BEN-YAKAR
金额：
$ 61.57万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8181677
关键词：
Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Model Animals Area Behavior Behavioral Biological Assay Brain Caenorhabditis elegans Chemicals Cognition Complement Detection Development Disease Disease model Drug Delivery Systems Fluorescence Functional disorder Genetic Genetic Models Glutamates Goals Health Hour Human Huntington Disease In Vitro Individual Knowledge Lasers Maps Marriage Methods Microfluidics Modeling Morphology Nerve Degeneration Nervous system structure Neurobiology Neurons Optical Methods Optics Parkinson Disease Pathway interactions Performance Pharmaceutical Preparations Population Preclinical Drug Evaluation Prevention Reporter Research Resolution Scanning Screening procedure Speed System Time base cholinergic combinatorial detector drug candidate drug development drug synthesis functional decline high throughput screening in vivo in vivo Model instrumentation millisecond nervous system disorder novel prevent small molecule libraries

项目摘要

DESCRIPTION (provided by applicant): The specific problems in behaviors and cognition that are caused by major neurological diseases including Alzheimer's, Parkinson's, Huntington's, and ALS arise due to the progressive degeneration and dysfunction of neurons in selected regions throughout the brain. Similar causes are also hypothesized for the common decline in behaviors and cognition associated with natural aging. Yet, the entire complement of neurons that become progressively dysmorphic and dysfunctional through natural aging remains unknown. A paradigm shifting approach for discovering drugs that prevent neurodegeneration through natural aging and disease models would be to study the effect of each chemical compound in the entire nervous system of a well-defined model organism in a high-throughput manner. We propose to develop a novel high-throughput screening platform using optics and microfluidics (opto-fluidics) that will enable characterization of each neuron in the whole nervous system within milliseconds with sub-cellular resolution in the genetic model Caenorhabditis elegans. The marriage of an ultra-rapid screening method with novel in vivo models will open the possibility for unbiased screens that do not require any prior knowledge of potential drug targets and pathways. We have chosen C. elegans because it is the only animal with a completely characterized nervous system, is amenable to high-throughput drug screening with microfluidics, and is a validated model for aging and neurological diseases in humans. The proposed opto-fluidics platform will be able to rapidly quantify the morphological integrity of every neuron in an animal's nervous system in milliseconds as they pass through a microfludic channel. Individual neurons can easily be identified by combinatorial expression of diverse fluorescent reporters in a single animal. Besides high-speed quantification capabilities, the ability to automatically interface with 96- or 384-well plates will enable for loading of a large number of populations of worms each treated with a different chemical compound into the opto-fluidics chip. The principles uncovered from these studies will have a profound impact on understanding the neuronal basis for how behavioral performance declines in disease and aging, and how to prevent this decline in humans. PUBLIC HEALTH RELEVANCE:

描述（由申请人提供）：由主要神经系统疾病（包括阿尔茨海默病、帕金森病、亨廷顿舞蹈症和肌萎缩侧索硬化症）引起的行为和认知方面的具体问题是由于整个大脑选定区域的神经元进行性退化和功能障碍而引起的。与自然衰老相关的行为和认知普遍下降也有类似的假设。然而，由于自然衰老而逐渐畸形和功能障碍的整个神经元仍然未知。通过自然衰老和疾病模型发现预防神经退行性变的药物的范式转变方法是以高通量方式研究每种化合物在明确的模型生物体的整个神经系统中的作用。我们建议使用光学和微流体（光流体）开发一种新型高通量筛选平台，该平台将能够在毫秒内以亚细胞分辨率表征秀丽隐杆线虫遗传模型中整个神经系统中的每个神经元。超快速筛选方法与新颖的体内模型的结合将为公正的筛选提供可能性，这种筛选不需要任何潜在药物靶点和途径的先验知识。我们选择秀丽隐杆线虫是因为它是唯一具有完全特征化神经系统的动物，适合使用微流体进行高通量药物筛选，并且是人类衰老和神经系统疾病的经过验证的模型。所提出的光流体平台将能够在动物神经系统中的每个神经元通过微流体通道时在几毫秒内快速量化它们的形态完整性。通过单个动物中不同荧光报告基因的组合表达，可以轻松识别单个神经元。除了高速定量功能外，与 96 孔板或 384 孔板自动连接的能力将能够将大量蠕虫群体加载到光流控芯片中，每种蠕虫群体都经过不同的化合物处理。这些研究揭示的原理将对理解疾病和衰老中行为表现如何下降的神经元基础以及如何预防人类的这种下降产生深远的影响。公共卫生相关性：