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Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin α1-antitrypsin Z

Gosai, SJ and Kwak, JH and Luke, CJ and Long, OS and King, DE and Kovatch, KJ and Johnston, PA and Shun, TY and Lazo, JS and Perlmutter, DH and Silverman, GA and Pak, SC (2010) Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin α1-antitrypsin Z. PLoS ONE, 5 (11).

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The development of preclinical models amenable to live animal bioactive compound screening is an attractive approach to discovering effective pharmacological therapies for disorders caused by misfolded and aggregation-prone proteins. In general, however, live animal drug screening is labor and resource intensive, and has been hampered by the lack of robust assay designs and high throughput work-flows. Based on their small size, tissue transparency and ease of cultivation, the use of C. elegans should obviate many of the technical impediments associated with live animal drug screening. Moreover, their genetic tractability and accomplished record for providing insights into the molecular and cellular basis of human disease, should make C. elegans an ideal model system for in vivo drug discovery campaigns. The goal of this study was to determine whether C. elegans could be adapted to high-throughput and high-content drug screening strategies analogous to those developed for cell-based systems. Using transgenic animals expressing fluorescently-tagged proteins, we first developed a high-quality, high-throughput work-flow utilizing an automated fluorescence microscopy platform with integrated image acquisition and data analysis modules to qualitatively assess different biological processes including, growth, tissue development, cell viability and autophagy. We next adapted this technology to conduct a small molecule screen and identified compounds that altered the intracellular accumulation of the human aggregation prone mutant that causes liver disease in α1-antitrypsin deficiency. This study provides powerful validation for advancement in preclinical drug discovery campaigns by screening live C. elegans modeling α1-antitrypsin deficiency and other complex disease phenotypes on high-content imaging platforms.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Gosai, SJ
Kwak, JH
Luke, CJcjl16@pitt.eduCJL16
Long, OS
King, DE
Kovatch, KJ
Johnston, PApaj18@pitt.eduPAJ180000-0001-5815-3091
Shun, TYtos8@pitt.eduTOS8
Lazo, JSlazo@pitt.eduLAZO
Perlmutter, DHdhp6@pitt.eduDHP6
Silverman, GAgas12@pitt.eduGAS12
Pak, SCscp10@pitt.eduSCP10
ContributionContributors NameEmailPitt UsernameORCID
Date: 9 December 2010
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 5
Number: 11
DOI or Unique Handle: 10.1371/journal.pone.0015460
Schools and Programs: School of Medicine > Cell Biology and Molecular Physiology
Refereed: Yes
MeSH Headings: Animals; Autophagy--drug effects; Caenorhabditis elegans--drug effects; Caenorhabditis elegans--genetics; Caenorhabditis elegans--metabolism; Cantharidin--pharmacology; Cell Survival--drug effects; Dopamine Antagonists--pharmacology; Drug Evaluation, Preclinical--methods; Enzyme Inhibitors--pharmacology; Fluphenazine--pharmacology; Humans; Luminescent Proteins--genetics; Luminescent Proteins--metabolism; Microscopy, Fluorescence--methods; Models, Animal; Pimozide--pharmacology; Sodium Azide--pharmacology; alpha 1-Antitrypsin--genetics; alpha 1-Antitrypsin--metabolism
Other ID: NLM PMC2980495
PubMed Central ID: PMC2980495
PubMed ID: 21103396
Date Deposited: 22 Aug 2012 21:54
Last Modified: 12 Sep 2019 19:55


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