Engineering Circadian Biology into Induced Pluripotent Stem Cell Organ-on-a-Chip Models

将昼夜节律生物学工程转化为诱导多能干细胞器官芯片模型

基本信息

  • 批准号:
    NC/X002152/1
  • 负责人:
  • 金额:
    $ 25.72万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2023
  • 资助国家:
    英国
  • 起止时间:
    2023 至 无数据
  • 项目状态:
    未结题

项目摘要

Organ-on-a chip (OOAC) devices are an emerging tool for studying how organs function and for testing new and repurposed drugs in a laboratory environment. Each chip contains hollow channels containing combinations of human cells that interact with each other to mimic the functioning of our organs. Mechanical forces can be applied to replicate the physical forces that cells experience in our tissues and organs, for example fluid flow and stretch for the heart and blood vessels. Ultimately OOAC systems may be used to reduce the use of animals in research and ultimately to replace routine use of animals altogether.All tissues in the body have an internal biological circadian 'clock' which co-ordinates cellular processes in our tissues and organs according to the time of day or night, creating cycles of biological function every 24h. Importantly drug effectiveness and toxicity often varies according to the time of administration, which means that there may be times of day when a drug is most effective and produces the least side effects. However, for the majority of treatments, the influence of biological time on therapeutic effectiveness has not been studied or exploited. This is partly because the early stages of a drug development, involving simple cell systems and then animal models do not replicate the human circadian clock. Accordingly, the first time a novel drug encounters a relevant human circadian clock is during phase I clinical trials many years into the development process. This results in costly late-stage failure of drug discovery programmes and the unnecessary use of animals in earlier stages of development. Currently circadian rhythms are not incorporated into OOAC technology and there is no means of establishing the biological time of cells within these devices, limiting the therapeutic and commercial potential of the technology. The overall aim of this project is, therefore, to incorporate the circadian clock into OOAC systems, allowing the cellular 'time of day' to be monitored and for drugs to be tested at different time points that reflect day and night for our organs.In this project we will develop cell lines from Induced Pluripotent Stem Cells (iPSCs) that are able to 'report' the time of the circadian clock. This involves using the gene editing technique CRISPR to link a luminescent tag to key genes that control the clock. Cellular circadian rhythms can then be induced and monitored non-invasively. iPSCs can be differentiated into all cell types in the body allowing us to develop a library of novel human iPSC-derived differentiated clock reporter cells. In this project we will turn the iPSCs into endothelial cells which line our blood vessels and skeletal muscle cells. The cells will be grown in OOAC devices and stimuli will be provided that 'set the time' of the clock resulting in the expression of clock genes, measured by luminescence, that will oscillate over a 24hr period. We will use a variety of stimuli to 'set the time' of the clock including chemical factors, such as growth factors and glucocorticoids, but also mechanical stimuli, such as fluid flow and stretch which are integral to OOAC devices. Finally we will look at whether known drugs have a different effect on the cells depending on when it is administered during the 24hr circadian rhythm. The ability to incorporate biological time into OOAC systems will make the systems better able to replicate the functioning of organs in our bodies and enhance their ability to be used as laboratory systems to replace the routine use of animals in research.
芯片上器官(OOAC)设备是一种新兴的工具,用于研究器官的功能,并在实验室环境中测试新的和重新用途的药物。每个芯片都含有中空通道,其中含有人体细胞的组合,这些细胞相互作用以模仿我们器官的功能。可以施加机械力来复制细胞在我们的组织和器官中所经历的物理力,例如心脏和血管的流体流动和拉伸。最终,OOAC系统可以减少研究中使用动物,并最终完全取代常规使用动物。人体内的所有组织都有一个内部生物昼夜节律“钟”,它根据白天或黑夜的时间协调我们组织和器官中的细胞过程,每24小时产生一次生物功能循环。重要的是,药物的有效性和毒性通常会根据给药时间而变化,这意味着一天中可能会有药物最有效且副作用最少的时间。然而,对于大多数治疗,尚未研究或利用生物时间对治疗效果的影响。这部分是因为药物开发的早期阶段,涉及简单的细胞系统,然后是动物模型,不能复制人类的生物钟。因此,新药第一次遇到相关的人类生物钟是在开发过程中多年的I期临床试验期间。这导致药物发现计划后期失败,代价高昂,并在早期开发阶段不必要地使用动物。目前,昼夜节律没有被纳入OOAC技术,并且没有在这些设备内建立细胞的生物时间的手段,限制了该技术的治疗和商业潜力。因此,该项目的总体目标是将生物钟纳入OOAC系统,从而能够监测细胞的“一天中的时间”,并在不同的时间点测试药物,以反映我们器官的昼夜。在该项目中,我们将从诱导多能干细胞(iPSCs)中开发出能够“报告”生物钟时间的细胞系。这涉及到使用基因编辑技术CRISPR将发光标签与控制生物钟的关键基因联系起来。然后可以非侵入性地诱导和监测细胞的昼夜节律。iPSC可以分化成体内的所有细胞类型,使我们能够开发新的人iPSC衍生的分化的时钟报告细胞库。在这个项目中,我们将把iPSC变成内皮细胞,这些细胞排列在我们的血管和骨骼肌细胞中。细胞将在OOAC装置中生长,并且将提供刺激,该刺激“设定”时钟的时间,从而导致通过发光测量的时钟基因的表达,该时钟基因将在24小时的时间段内振荡。我们将使用各种刺激来“设定”时钟的时间,包括化学因素,如生长因子和糖皮质激素,以及机械刺激,如流体流动和拉伸,这是OOAC设备不可或缺的。最后,我们将研究已知药物是否对细胞产生不同的影响,这取决于在24小时昼夜节律期间何时施用。将生物时间纳入OOAC系统的能力将使该系统能够更好地复制我们体内器官的功能,并提高其作为实验室系统的能力,以取代研究中常规使用的动物。

项目成果

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David Alan Lee其他文献

David Alan Lee的其他文献

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{{ truncateString('David Alan Lee', 18)}}的其他基金

BBSRC IAA Queen Mary University of London
BBSRC IAA 伦敦玛丽女王大学
  • 批准号:
    BB/X511067/1
  • 财政年份:
    2022
  • 资助金额:
    $ 25.72万
  • 项目类别:
    Research Grant
Mechno-regulation of genome function to direct stem cell fate
基因组功能的机械调节指导干细胞的命运
  • 批准号:
    BB/N018532/1
  • 财政年份:
    2017
  • 资助金额:
    $ 25.72万
  • 项目类别:
    Research Grant
Platform Grant: Multiscale Mechanobiology for Tissue Engineering
平台资助:组织工程的多尺度力学生物学
  • 批准号:
    EP/E046975/1
  • 财政年份:
    2007
  • 资助金额:
    $ 25.72万
  • 项目类别:
    Research Grant
Queen Mary, University of London - Discipline Bridging Initiative
伦敦大学玛丽皇后学院 - 学科桥梁计划
  • 批准号:
    G0502256/1
  • 财政年份:
    2006
  • 资助金额:
    $ 25.72万
  • 项目类别:
    Research Grant

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NSF Postdoctoral Fellowship in Biology: Investigating a Novel Circadian Time-Keeping Mechanism Revealed by Environmental Manipulation
美国国家科学基金会生物学博士后奖学金:研究环境操纵揭示的新型昼夜节律机制
  • 批准号:
    2305609
  • 财政年份:
    2024
  • 资助金额:
    $ 25.72万
  • 项目类别:
    Fellowship Award
Investigating the ecological functioning of the plant phyllosphere microbiome in the context of circadian biology.
在昼夜节律生物学的背景下研究植物叶际微生物组的生态功能。
  • 批准号:
    2872880
  • 财政年份:
    2023
  • 资助金额:
    $ 25.72万
  • 项目类别:
    Studentship
NSF Postdoctoral Fellowship in Biology FY 2022: C.R.I.C.K.E.T.S. – Circadian Rhythms In Crickets: linKing Evolution, Timing, and Selection
2022 财年 NSF 生物学博士后奖学金:C.R.I.C.K.E.T.S.
  • 批准号:
    2208928
  • 财政年份:
    2023
  • 资助金额:
    $ 25.72万
  • 项目类别:
    Fellowship Award
Chronomedical inovation based on circadian biology
基于昼夜节律生物学的时间医学创新
  • 批准号:
    22H04987
  • 财政年份:
    2022
  • 资助金额:
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  • 项目类别:
    Grant-in-Aid for Scientific Research (S)
Impacts of Sleep and Circadian Biology on Alzheimer's Disease and Aging: A Focus on Genetics and Genomics
睡眠和昼夜节律生物学对阿尔茨海默病和衰老的影响:关注遗传学和基因组学
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    10606644
  • 财政年份:
    2021
  • 资助金额:
    $ 25.72万
  • 项目类别:
Chemical Biology Approaches for Studying Circadian Rhythms
研究昼夜节律的化学生物学方法
  • 批准号:
    10437920
  • 财政年份:
    2021
  • 资助金额:
    $ 25.72万
  • 项目类别:
CAREER: A Systems Biology Approach to Determine How Information from the Cellular Environment is Transduced to the Circadian Clock.
职业:一种系统生物学方法,用于确定来自细胞环境的信息如何转换为昼夜节律时钟。
  • 批准号:
    2045674
  • 财政年份:
    2021
  • 资助金额:
    $ 25.72万
  • 项目类别:
    Continuing Grant
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2021
  • 资助金额:
    $ 25.72万
  • 项目类别:
    Postdoctoral Fellowships
Impacts of Sleep and Circadian Biology on Alzheimer's Disease and Aging: A Focus on Genetics and Genomics
睡眠和昼夜节律生物学对阿尔茨海默病和衰老的影响:关注遗传学和基因组学
  • 批准号:
    10237478
  • 财政年份:
    2021
  • 资助金额:
    $ 25.72万
  • 项目类别:
Impacts of Sleep and Circadian Biology on Alzheimer's Disease and Aging: A Focus on Genetics and Genomics
睡眠和昼夜节律生物学对阿尔茨海默病和衰老的影响:关注遗传学和基因组学
  • 批准号:
    10378650
  • 财政年份:
    2021
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