Mol Cell Proteomics, Jun 2021

Proteomic Portraits Reveal Evolutionarily Conserved and Divergent Responses to Spinal Cord Injury


Michael A Skinnider, Jason Rogalski, Seth Tigchelaar, Neda Manouchehri, Anna Prudova, Angela M Jackson, Karina Nielsen, Jaihyun Jeong, Shalini Chaudhary, Katelyn Shortt, Ylonna Gallagher-Kurtzke, Kitty So, Allan Fong, Rishab Gupta, Elena B Okon, Michael A Rizzuto, Kevin Dong, Femke Streijger, Lise Belanger, Leanna Ritchie, Angela Tsang, Sean Christie, Jean-Marc Mac-Thiong, Christopher Bailey, Tamir Ailon, Raphaele Charest-Morin, Nicolas Dea, Jefferson R Wilson, Sanjay Dhall, Scott Paquette, John Street, Charles G Fisher, Marcel F Dvorak, Casey Shannon, Christoph Borchers, Robert Balshaw, Leonard J Foster, Brian K Kwon

 

Despite the emergence of promising therapeutic approaches in preclinical studies, the failure of large-scale clinical trials leaves clinicians without effective treatments for acute spinal cord injury (SCI). These trials are hindered by their reliance on detailed neurological examinations to establish outcomes, which inflate the time and resources required for completion. Moreover, therapeutic development takes place in animal models whose relevance to human injury remains unclear. Here, we address these challenges through targeted proteomic analyses of cerebrospinal fluid and serum samples from 111 patients with acute SCI and, in parallel, a large animal (porcine) model of SCI. We develop protein biomarkers of injury severity and recovery, including a prognostic model of neurological improvement at 6 months with an area under the receiver operating characteristic curve of 0.91, and validate these in an independent cohort. Through cross-species proteomic analyses, we dissect evolutionarily conserved and divergent aspects of the SCI response and establish the cerebrospinal fluid abundance of glial fibrillary acidic protein as a biochemical outcome measure in both humans and pigs. Our work opens up new avenues to catalyze translation by facilitating the evaluation of novel SCI therapies, while also providing a resource from which to direct future preclinical efforts.

 

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