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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...

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Autores principales: Martinez, Briana I., Mousa, Gergey Alzaem, Fleck, Kiera, MacCulloch, Tara, Diehnelt, Chris W., Stephanopoulos, Nicholas, Stabenfeldt, Sarah E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
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.
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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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