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Engineering Synthetic Signaling Pathways with Programmable dCas9-Based Chimeric Receptors
Synthetic receptors provide a powerful experimental tool for generation of designer cells capable of monitoring the environment, sensing specific input signals, and executing diverse custom response programs. To advance the promise of cellular engineering, we have developed a class of chimeric recep...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608971/ https://www.ncbi.nlm.nih.gov/pubmed/28903044 http://dx.doi.org/10.1016/j.celrep.2017.08.044 |
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author | Baeumler, Toni A. Ahmed, Ahmed Ashour Fulga, Tudor A. |
author_facet | Baeumler, Toni A. Ahmed, Ahmed Ashour Fulga, Tudor A. |
author_sort | Baeumler, Toni A. |
collection | PubMed |
description | Synthetic receptors provide a powerful experimental tool for generation of designer cells capable of monitoring the environment, sensing specific input signals, and executing diverse custom response programs. To advance the promise of cellular engineering, we have developed a class of chimeric receptors that integrate a highly programmable and portable nuclease-deficient CRISPR/Cas9 (dCas9) signal transduction module. We demonstrate that the core dCas9 synthetic receptor (dCas9-synR) architecture can be readily adapted to various classes of native ectodomain scaffolds, linking their natural inputs with orthogonal output functions. Importantly, these receptors achieved stringent OFF/ON state transition characteristics, showed agonist-mediated dose-dependent activation, and could be programmed to couple specific disease markers with diverse, therapeutically relevant multi-gene expression circuits. The modular dCas9-synR platform developed here provides a generalizable blueprint for designing next generations of synthetic receptors, which will enable the implementation of highly complex combinatorial functions in cellular engineering. |
format | Online Article Text |
id | pubmed-5608971 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-56089712017-09-29 Engineering Synthetic Signaling Pathways with Programmable dCas9-Based Chimeric Receptors Baeumler, Toni A. Ahmed, Ahmed Ashour Fulga, Tudor A. Cell Rep Article Synthetic receptors provide a powerful experimental tool for generation of designer cells capable of monitoring the environment, sensing specific input signals, and executing diverse custom response programs. To advance the promise of cellular engineering, we have developed a class of chimeric receptors that integrate a highly programmable and portable nuclease-deficient CRISPR/Cas9 (dCas9) signal transduction module. We demonstrate that the core dCas9 synthetic receptor (dCas9-synR) architecture can be readily adapted to various classes of native ectodomain scaffolds, linking their natural inputs with orthogonal output functions. Importantly, these receptors achieved stringent OFF/ON state transition characteristics, showed agonist-mediated dose-dependent activation, and could be programmed to couple specific disease markers with diverse, therapeutically relevant multi-gene expression circuits. The modular dCas9-synR platform developed here provides a generalizable blueprint for designing next generations of synthetic receptors, which will enable the implementation of highly complex combinatorial functions in cellular engineering. Cell Press 2017-09-12 /pmc/articles/PMC5608971/ /pubmed/28903044 http://dx.doi.org/10.1016/j.celrep.2017.08.044 Text en Crown Copyright © 2017 Published by Elsevier Inc. All rights reserved. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Baeumler, Toni A. Ahmed, Ahmed Ashour Fulga, Tudor A. Engineering Synthetic Signaling Pathways with Programmable dCas9-Based Chimeric Receptors |
title | Engineering Synthetic Signaling Pathways with Programmable dCas9-Based Chimeric Receptors |
title_full | Engineering Synthetic Signaling Pathways with Programmable dCas9-Based Chimeric Receptors |
title_fullStr | Engineering Synthetic Signaling Pathways with Programmable dCas9-Based Chimeric Receptors |
title_full_unstemmed | Engineering Synthetic Signaling Pathways with Programmable dCas9-Based Chimeric Receptors |
title_short | Engineering Synthetic Signaling Pathways with Programmable dCas9-Based Chimeric Receptors |
title_sort | engineering synthetic signaling pathways with programmable dcas9-based chimeric receptors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608971/ https://www.ncbi.nlm.nih.gov/pubmed/28903044 http://dx.doi.org/10.1016/j.celrep.2017.08.044 |
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