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Uncovering temporospatial sensitive TBI targeting strategies via in vivo phage display
The heterogeneous pathophysiology of traumatic brain injury (TBI) is a barrier to advancing diagnostics and therapeutics, including targeted drug delivery. We used a unique discovery pipeline to identify novel targeting motifs that recognize specific temporal phases of TBI pathology. This pipeline c...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307250/ https://www.ncbi.nlm.nih.gov/pubmed/35867794 http://dx.doi.org/10.1126/sciadv.abo5047 |
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author | Martinez, Briana I. Mousa, Gergey Alzaem Fleck, Kiera MacCulloch, Tara Diehnelt, Chris W. Stephanopoulos, Nicholas Stabenfeldt, Sarah E. |
author_facet | Martinez, Briana I. Mousa, Gergey Alzaem Fleck, Kiera MacCulloch, Tara Diehnelt, Chris W. Stephanopoulos, Nicholas Stabenfeldt, Sarah E. |
author_sort | Martinez, Briana I. |
collection | PubMed |
description | The heterogeneous pathophysiology of traumatic brain injury (TBI) is a barrier to advancing diagnostics and therapeutics, including targeted drug delivery. We used a unique discovery pipeline to identify novel targeting motifs that recognize specific temporal phases of TBI pathology. This pipeline combined in vivo biopanning with domain antibody (dAb) phage display, next-generation sequencing analysis, and peptide synthesis. We identified targeting motifs based on the complementarity-determining region 3 structure of dAbs for acute (1 day post-injury) and subacute (7 days post-injury) post-injury time points in a preclinical TBI model (controlled cortical impact). Bioreactivity and temporal sensitivity of the targeting motifs were validated via immunohistochemistry. Immunoprecipitation–mass spectrometry indicated that the acute TBI targeting motif recognized targets associated with metabolic and mitochondrial dysfunction, whereas the subacute TBI motif was largely associated with neurodegenerative processes. This pipeline successfully discovered temporally specific TBI targeting motif/epitope pairs that will serve as the foundation for the next-generation targeted TBI therapeutics and diagnostics. |
format | Online Article Text |
id | pubmed-9307250 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-93072502022-08-09 Uncovering temporospatial sensitive TBI targeting strategies via in vivo phage display Martinez, Briana I. Mousa, Gergey Alzaem Fleck, Kiera MacCulloch, Tara Diehnelt, Chris W. Stephanopoulos, Nicholas Stabenfeldt, Sarah E. Sci Adv Biomedicine and Life Sciences The heterogeneous pathophysiology of traumatic brain injury (TBI) is a barrier to advancing diagnostics and therapeutics, including targeted drug delivery. We used a unique discovery pipeline to identify novel targeting motifs that recognize specific temporal phases of TBI pathology. This pipeline combined in vivo biopanning with domain antibody (dAb) phage display, next-generation sequencing analysis, and peptide synthesis. We identified targeting motifs based on the complementarity-determining region 3 structure of dAbs for acute (1 day post-injury) and subacute (7 days post-injury) post-injury time points in a preclinical TBI model (controlled cortical impact). Bioreactivity and temporal sensitivity of the targeting motifs were validated via immunohistochemistry. Immunoprecipitation–mass spectrometry indicated that the acute TBI targeting motif recognized targets associated with metabolic and mitochondrial dysfunction, whereas the subacute TBI motif was largely associated with neurodegenerative processes. This pipeline successfully discovered temporally specific TBI targeting motif/epitope pairs that will serve as the foundation for the next-generation targeted TBI therapeutics and diagnostics. American Association for the Advancement of Science 2022-07-22 /pmc/articles/PMC9307250/ /pubmed/35867794 http://dx.doi.org/10.1126/sciadv.abo5047 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Martinez, Briana I. Mousa, Gergey Alzaem Fleck, Kiera MacCulloch, Tara Diehnelt, Chris W. Stephanopoulos, Nicholas Stabenfeldt, Sarah E. Uncovering temporospatial sensitive TBI targeting strategies via in vivo phage display |
title | Uncovering temporospatial sensitive TBI targeting strategies via in vivo phage display |
title_full | Uncovering temporospatial sensitive TBI targeting strategies via in vivo phage display |
title_fullStr | Uncovering temporospatial sensitive TBI targeting strategies via in vivo phage display |
title_full_unstemmed | Uncovering temporospatial sensitive TBI targeting strategies via in vivo phage display |
title_short | Uncovering temporospatial sensitive TBI targeting strategies via in vivo phage display |
title_sort | uncovering temporospatial sensitive tbi targeting strategies via in vivo phage display |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307250/ https://www.ncbi.nlm.nih.gov/pubmed/35867794 http://dx.doi.org/10.1126/sciadv.abo5047 |
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