Large-scale microfluidics providing high-resolution and high-throughput screening of Caenorhabditis elegans poly-glutamine aggregation model.
Large-scale microfluidics providing high-resolution and high-throughput screening of Caenorhabditis elegans poly-glutamine aggregation model.
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DOI：
10.1038/ncomms13023
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发表时间：
2016-10-11
影响因子：
16.6
通讯作者：
Ben-Yakar, Adela
中科院分区：
文献类型：
--
作者：
Mondal, Sudip;Hegarty, Evan;Martin, Chris;Gokce, Sertan Kutal;Ghorashian, Navid;Ben-Yakar, Adela
下一代药物筛选可以从体内研究中获益，使用秀丽隐杆线虫等小动物模型进行命中识别和先导优化。目前的体内分析可以在高分辨率的低通量下操作，也可以在高通量的低分辨率下操作。为了实现秀丽隐杆线虫的高通量和高分辨率成像，我们开发了一个自动化微流控平台。该平台可以在16分钟内使用微米分辨率的大型芯片对来自96个不同种群的约4,000个秀丽隐杆线虫的15个z堆栈进行成像。利用该平台，我们在25个芯片上筛选了约10万只聚谷氨酰胺聚集模型动物。我们测试了约1000种fda批准的药物在改善模型聚集表型方面的功效，并确定了四种确认的效果。这个强大的平台现在能够以体外细胞检测的速度和成本对各种秀丽隐杆线虫疾病模型进行高含量筛选。在整个动物身上进行大规模筛选可以促进药物发现，但在技术上具有挑战性。在这里，Mondal等人开发了一种结合了自动成像平台的微流控芯片，可以实现对秀丽隐杆线虫疾病模型的高通量、高分辨率筛选。
Next generation drug screening could benefit greatly from in vivo studies, using small animal models such as Caenorhabditis elegans for hit identification and lead optimization. Current in vivo assays can operate either at low throughput with high resolution or with low resolution at high throughput. To enable both high-throughput and high-resolution imaging of C. elegans, we developed an automated microfluidic platform. This platform can image 15 z-stacks of ∼4,000 C. elegans from 96 different populations using a large-scale chip with a micron resolution in 16 min. Using this platform, we screened ∼100,000 animals of the poly-glutamine aggregation model on 25 chips. We tested the efficacy of ∼1,000 FDA-approved drugs in improving the aggregation phenotype of the model and identified four confirmed hits. This robust platform now enables high-content screening of various C. elegans disease models at the speed and cost of in vitro cell-based assays. Large-scale screens on whole animals could facilitate drug discovery, but are technically challenging. Here, Mondal et al. develop a microfluidic chip combined with an automated imaging platform that enables high-throughput, high-resolution screening of Caenorhabditis elegans disease models.
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影响因子：
158.5
作者：
Hohnloser, Stefan H.;Crijns, Harry J. G. M.;Connolly, Stuart J.
通讯作者：
Connolly, Stuart J.
影响因子：
4.7
作者：
Artal-Sanz, Marto;de Jong, Liesbeth;Tavernarakis, Nektarios
通讯作者：
Tavernarakis, Nektarios
影响因子：
6.1
作者：
Hulme, S. Elizabeth;Shevkoplyas, Sergey S.;Whitesides, George M.
通讯作者：
Whitesides, George M.
DOI：
10.1073/pnas.90.24.12045
发表时间：
1993-12-15
影响因子：
11.1
作者：
DAIGLE, I;LI, C
通讯作者：
LI, C
影响因子：
14.8
作者：
Calamini, Barbara;Silva, Maria Catarina;Madoux, Franck;Hutt, Darren M.;Khanna, Shilpi;Chalfant, Monica A.;Saldanha, S. Adrian;Hodder, Peter;Tait, Bradley D.;Garza, Dan;Balch, William E.;Morimoto, Richard I.
通讯作者：
Morimoto, Richard I.