دورية أكاديمية
Machine intelligence identifies soluble TNFa as a therapeutic target for spinal cord injury
| العنوان: | Machine intelligence identifies soluble TNFa as a therapeutic target for spinal cord injury |
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| المؤلفون: | Huie, J. R., Ferguson, A. R., Kyritsis, N., Pan, J. Z., Irvine, K.-A., Nielson, J. L., Schupp, P. G., Oldham, M. C., Gensel, J. C., Lin, A., Segal, M. R., Ratan, R. R., Bresnahan, J. C., Beattie, M. S. |
| المساهمون: | NIH, NYSCoRE |
| المصدر: | Scientific Reports ; volume 11, issue 1 ; ISSN 2045-2322 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Multidisciplinary |
| الوصف: | Traumatic spinal cord injury (SCI) produces a complex syndrome that is expressed across multiple endpoints ranging from molecular and cellular changes to functional behavioral deficits. Effective therapeutic strategies for CNS injury are therefore likely to manifest multi-factorial effects across a broad range of biological and functional outcome measures. Thus, multivariate analytic approaches are needed to capture the linkage between biological and neurobehavioral outcomes. Injury-induced neuroinflammation (NI) presents a particularly challenging therapeutic target, since NI is involved in both degeneration and repair. Here, we used big-data integration and large-scale analytics to examine a large dataset of preclinical efficacy tests combining five different blinded, fully counter-balanced treatment trials for different acute anti-inflammatory treatments for cervical spinal cord injury in rats. Multi-dimensional discovery, using topological data analysis (TDA) and principal components analysis (PCA) revealed that only one showed consistent multidimensional syndromic benefit: intrathecal application of recombinant soluble TNFα receptor 1 (sTNFR1), which showed an inverse-U dose response efficacy. Using the optimal acute dose, we showed that clinically-relevant 90 min delayed treatment profoundly affected multiple biological indices of NI in the first 48 h after injury, including reduction in pro-inflammatory cytokines and gene expression of a coherent complex of acute inflammatory mediators and receptors. Further, a 90 min delayed bolus dose of sTNFR1 reduced the expression of NI markers in the chronic perilesional spinal cord, and consistently improved neurological function over 6 weeks post SCI. These results provide validation of a novel strategy for precision preclinical drug discovery that is likely to improve translation in the difficult landscape of CNS trauma, and confirm the importance of TNFα signaling as a therapeutic target. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41598-021-82951-5 |
| الإتاحة: | https://doi.org/10.1038/s41598-021-82951-5Test https://www.nature.com/articles/s41598-021-82951-5.pdfTest https://www.nature.com/articles/s41598-021-82951-5Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.5D2413EB |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41598-021-82951-5 |
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