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基于表型的 IGF1R-PI3K-Akt-Tor 作用分析的整体生物体平台的开发。

Development of a Whole Organism Platform for Phenotype-Based Analysis of IGF1R-PI3K-Akt-Tor Action.

机构信息

The Key Laboratory of Mariculture, Education Ministry of China and College of Fisheries, Ocean University of China, Qingdao, 266003, China.

Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA.

出版信息

Sci Rep. 2017 May 17;7(1):1994. doi: 10.1038/s41598-017-01687-3.

DOI:10.1038/s41598-017-01687-3
PMID:28515443
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5435685/
Abstract

Aberrant regulation of the insulin-like growth factor (IGF)/insulin (IIS)-PI3K-AKT-TOR signaling pathway is linked to major human diseases, and key components of this pathway are targets for therapeutic intervention. Current assays are molecular target- or cell culture-based platforms. Due to the great in vivo complexities inherited in this pathway, there is an unmet need for whole organism based assays. Here we report the development of a zebrafish transgenic line, Tg(igfbp5a:GFP), which faithfully reports the mitotic action of IGF1R-PI3K-Akt-Tor signaling in epithelial cells in real-time. This platform is well suited for high-throughput assays and real-time cell cycle analysis. Using this platform, the dynamics of epithelial cell proliferation in response to low [Ca] stress and the distinct roles of Torc1 and Torc2 were elucidated. The availability of Tg(igfbp5a:GFP) line provides a whole organism platform for phenotype-based discovery of novel players and inhibitors in the IIS-PI3K-Akt-Tor signaling pathway.

摘要

胰岛素样生长因子 (IGF)/胰岛素 (IIS)-PI3K-AKT-TOR 信号通路的异常调节与人类主要疾病有关，该通路的关键组成部分是治疗干预的靶点。目前的测定方法是基于分子靶标或细胞培养的平台。由于该通路中存在着巨大的体内复杂性，因此需要基于整个生物体的测定方法。在这里，我们报告了一种斑马鱼转基因系 Tg(igfbp5a:GFP)的开发，该转基因系能够实时忠实地报告 IGF1R-PI3K-Akt-Tor 信号在上皮细胞中的有丝分裂作用。该平台非常适合高通量测定和实时细胞周期分析。利用该平台，阐明了上皮细胞对低钙应激的增殖反应的动力学以及 Torc1 和 Torc2 的不同作用。Tg(igfbp5a:GFP)系的出现为基于表型的 IIS-PI3K-Akt-Tor 信号通路中新型参与者和抑制剂的发现提供了一个完整的生物体平台。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/2872439b8b85/41598_2017_1687_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/a26a08cf14ea/41598_2017_1687_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/d07c1bcde8e6/41598_2017_1687_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/3eb3b31fb4e6/41598_2017_1687_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/155de53aa00e/41598_2017_1687_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/d1f7913c41e8/41598_2017_1687_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/4f80ce34e2f0/41598_2017_1687_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/2872439b8b85/41598_2017_1687_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/a26a08cf14ea/41598_2017_1687_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/d07c1bcde8e6/41598_2017_1687_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/3eb3b31fb4e6/41598_2017_1687_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/155de53aa00e/41598_2017_1687_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/d1f7913c41e8/41598_2017_1687_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/4f80ce34e2f0/41598_2017_1687_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b476/5435685/2872439b8b85/41598_2017_1687_Fig7_HTML.jpg

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