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

• 批准号: 8856453
• 负责人: ADELA BEN-YAKAR
• 金额: $ 53.67万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856453
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Animals; Area; Behavior; Behavioral; Biological Assay; Brain; Caenorhabditis elegans; Chemicals; Cognition; Complement; Detection; Development; Disease; Disease model; Drug Targeting; 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; 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; screening; small molecule libraries

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.

描述（由申请人提供）：由于主要神经系统疾病，包括阿尔茨海默氏症，帕金森氏症，亨廷顿和ALS在内的主要神经系统疾病所引起的特定问题，这是由于整个大脑所选地区神经元的进行性变性和功能障碍而引起的。对于与自然衰老相关的行为和认知的普遍下降，也假设了类似的原因。然而，通过自然衰老逐渐变形和功能障碍的神经元的整个补体仍然未知。一种用于发现通过自然衰老和疾病模型来防止神经退行性的药物的范式转移方法将是以高通量方式研究每种化合物在整个神经系统中的作用。我们建议使用光学和微流体（光流体学）开发一种新型的高通量筛选平台，该平台将在遗传模型Caenorhabditis elegres elegans中具有亚细胞分辨率的整个神经系统中每个神经元的表征。超优化筛查方法与新型体内模型的结合将为无偏见的屏幕打开可能性，这些屏幕不需要任何可能的潜在药物靶标和途径的知识。我们之所以选择秀丽隐杆线虫，是因为它是唯一具有完全表征神经系统的动物，可以通过微流体筛查高通量药物筛查，并且是人类衰老和神经系统疾病的经过验证的模型。拟议的光流体平台将能够快速量化动物神经系统中每个神经元的形态完整性，因为它们通过微浮力通道。单个动物中各种荧光记者的组合表达可以很容易地识别单个神经元。除了高速定量功能外，与96或384孔板自动接口的能力还可以加载大量的蠕虫种群，每个蠕虫都用不同的化合物处理到光流体芯片中。从这些研究中发现的原则将对理解疾病和衰老的行为表现如何下降以及如何防止人类下降的神经元基础产生深远的影响。

项目成果

Systematic Functional Characterization of Human 21st Chromosome Orthologs in Caenorhabditis elegans.

秀丽隐杆线虫人类 21 号染色体直系同源物的系统功能表征。

• DOI: 10.1534/g3.118.200019
• 发表时间: 2018
• 期刊: G3 (Bethesda, Md.)
• 作者: Nordquist,SarahK;Smith,SofiaR;Pierce,JonathanT
• 通讯作者: Pierce,JonathanT

Small-molecule-mediated axonal branching in Caenorhabditis elegans.

秀丽隐杆线虫中小分子介导的轴突分支。

• DOI: 10.1002/cbic.201200712
• 发表时间: 2013
• 期刊: Chembiochem : a European journal of chemical biology
• 作者: Zlotkowski,Katherine;Pierce-Shimomura,Jon;Siegel,Dionicio
• 通讯作者: Siegel,Dionicio

Worming our way to Alzheimer's disease drug discovery.

• DOI: 10.1016/j.biopsych.2012.12.026
• 发表时间: 2013-03-01
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Iyer, Sangeetha;Pierce-Shimomura, Jonathan T.
• 通讯作者: Pierce-Shimomura, Jonathan T.

APP-Induced Patterned Neurodegeneration Is Exacerbated by APOE4 in Caenorhabditis elegans.

APOE4 加剧了秀丽隐杆线虫中 APP 诱导的模式性神经变性。

• DOI: 10.1534/g3.120.401486
• 发表时间: 2020
• 期刊: G3 (Bethesda, Md.)
• 作者: Sae-Lee,Wisath;Scott,LuisaL;Brose,Lotti;Encarnacion,AliyahJ;Shi,Ted;Kore,Pragati;Oyibo,LashaunO;Ye,Congxi;Rozmiarek,SusanK;Pierce,JonathanT
• 通讯作者: Pierce,JonathanT

An automated microfluidic device for time-lapse imaging of mouse embryonic stem cells.

一种用于小鼠胚胎干细胞延时成像的自动化微流体装置。

• DOI: 10.1063/1.5124057
• 发表时间: 2019
• 期刊: Biomicrofluidics
• 影响因子: 3.2
• 作者: Laing,AdamF;Tirumala,Venkat;Hegarty,Evan;Mondal,Sudip;Zhao,Peisen;Hamilton,WilliamB;Brickman,JoshuaM;Ben-Yakar,Adela
• 通讯作者: Ben-Yakar,Adela