Conformational Ligand-Directed Targeting of Calcium-Dependent Receptors in Acute Trauma

Authors

• Renata Pasqualini
• Christopher Markosian
• Daniela I Staquicini
• Andrey S Dobroff
• Esteban Dodero-Rojas
• Paul C Whitford
• E Magda Barbu
• Julianna K Bronk
• Marina Cardó-Vila
• Dawn R Christianson
• Emmanuel Dias-Neto
• Wouter H P Driessen
• Liliana Guzman-Rojas
• Serena Marchiò
• Diana N Nunes
• Francislon S de Oliveira
• Michael G Ozawa
• Bettina Proneth
• Roberto Rangel
• Tracey L Smith
• Glauco R Souza
• Fernanda I Staquicini
• Fenny H F Tang
• Wallace B Baze
• João C Setubal
• John W Burns
• Michael A Dubick
• Juri G Gelovani
• Andriy I Batchinsky
• Jon E Mogford
• Charles E Wade
• John B Holcomb
• Stephen K Burley
• José N Onuchic
• Wadih Arap

Language

English

Publication Date

7-11-2025

Journal

Med

DOI

10.1016/j.medj.2025.100638

PMID

40609540

PMCID

PMC12955825

PubMedCentral® Posted Date

3-27-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: Trauma is a leading cause of mortality, but injury-specific molecular targets remain largely unknown. We hypothesized that distinctive yet unrecognized tissue targets accessible to circulating ligands might emerge during trauma, thereby underscoring a trauma-related proteome.

Methods: We screened a peptide library to discover targets in a porcine model of major trauma: compound femur fracture with hemorrhagic shock. Bioinformatics yielded conserved motifs, and candidate receptors were affinity purified. In silico and in vitro approaches served to investigate possible associations between candidate receptors and calcium, a major component of skeletal muscle and bone. In vivo homing and molecular imaging (PET/MRI and SPECT/CT) studies of the most promising ligand peptide candidate were performed in the porcine model and were also confirmed in a corresponding rat model of major trauma. Optical methodologies and molecular dynamics simulations served to explore the molecular attributes of the ligand-receptor binding.

Findings: Nearly all molecular targets of the selected ligand peptides were calcium-dependent proteins, which become accessible upon trauma. We validated specific binding of homing peptides to these receptors in injured tissues, including CLRGFPALVC:CASQ1, CSEIGVRAC:HSP27, and CRQRPASGC:CALR. Notably, we determined that ligand peptide CRQRPASGC targets an injury-specific calcium-facilitated conformation of calreticulin, enabling specific molecular imaging of trauma.

Conclusions: We conceptually propose the term "traumome" for the functional receptor repertoire that becomes readily amenable for ligand-directed targeting upon major trauma. These preclinical findings pave the way toward clinic-ready targeted theragnostic approaches in the setting of trauma.

Funding: Major funding was provided by the Defense Advanced Research Projects Agency (DARPA).

Keywords

Animals, Ligands, Rats, Swine, Femoral Fractures, Calcium, Shock, Hemorrhagic, Peptide Library, Disease Models, Animal, Male, acute trauma, calcium, calreticulin, compound fracture, in vivo screening, peptide library, phage display, receptor, shock, trauma-related proteome

Published Open-Access

yes

Recommended Citation

Pasqualini, Renata; Markosian, Christopher; Staquicini, Daniela I; et al., "Conformational Ligand-Directed Targeting of Calcium-Dependent Receptors in Acute Trauma" (2025). Faculty, Staff and Student Publications. 4526.
https://digitalcommons.library.tmc.edu/uthmed_docs/4526