Abstract
Neurotrauma especially traumatic brain injury (TBI) is the leading cause of death and disability worldwide. To improve upon the early diagnosis and develop precision-targeted therapies for TBI, it is critical to understand the underlying molecular mechanisms and signaling pathways. The transcription factor, nuclear factor kappa B (NFκB), which is ubiquitously expressed, plays a crucial role in the normal cell survival, proliferation, differentiation, function, as well as in disease states like neuroinflammation and neurodegeneration. Here, we hypothesized that real-time noninvasive bioluminescence molecular imaging allows rapid and precise monitoring of TBI-induced immediate and rapid spatio-temporal activation of NFκB signaling pathway in response to Glia maturation factor (GMF) upregulation which in turn leads to neuroinflammation and neurodegeneration post-TBI. To test and validate our hypothesis and to gain novel mechanistic insights, we subjected NFκB-RE-Luc transgenic male and female mice to TBI and performed real-time noninvasive bioluminescence imaging (BLI) as well as photoacoustic and ultrasound imaging (PAI). Our BLI data revealed that TBI leads to an immediate and sustained activation of NFκB signaling. Further, our BLI data suggest that especially in male NFκB-RE-Luc transgenic mice subjected to TBI, in addition to brain, there is widespread activation of NFκB signaling in multiple organs. However, in the case of the female NFκB-RE-Luc transgenic mice, TBI induces a very specific and localized activation of NFκB signaling in the brain. Further, our microRNA data suggest that TBI induces significant upregulation of mir-9-5p, mir-21a-5p, mir-34a-5p, mir-16-3p, as well as mir-155-5p within 24 h and these microRNAs can be successfully used as TBI-specific biomarkers. To the best of our knowledge, this is one of the first and unique study of its kind to report immediate and sustained activation of NFκB signaling post-TBI in a gender-specific manner by utilizing real-time non-invasive BLI and PAI in NFκB-RE-Luc transgenic mice. Our study will prove immensely beneficial to gain novel mechanistic insights underlying TBI, unravel novel therapeutic targets, as well as enable us to monitor in real-time the response to innovative TBI-specific precision-targeted gene and stem cell-based precision medicine.
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Acknowledgements
Research was sponsored by the Leonard Wood Institute in cooperation with the US Army Research Laboratory and was accomplished under Cooperative Agreement Number W911NF-14-2-0034. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the Leonard Wood Institute, the Army Research Laboratory or the US Government. The US Government is authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation hereon. The authors express their gratitude for the Acute Effects of Neurotrauma Consortium in assisting and coordinating the conduct of this project at Fort Leonard Wood. The authors graciously acknowledge the use of the IVIS Spectrum at the Harry S. Truman VA Biomolecular Imaging Core Facility and VisualSonics Vevo 2100 Imaging System at the University of Missouri Dalton Cardiovascular Research Center. This research was also supported by NIH Grant AG048205 and VA Research Career Scientist Award to AZ.
Funding
Research was sponsored by the Leonard Wood Institute in cooperation with the US Army Research Laboratory and was accomplished under Cooperative Agreement Number W911NF-14–2-0034. This research was also supported by NIH grant AG048205 and VA Research Career Scientist Award to AZ.
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SPR contributed to conceptualization and experimental study design, molecular imaging data acquisition, microRNA experiments, data analysis, and original draft preparation; MEA and RT performed immunofluorescence experiments, confocal microscopy, and data analysis; GPS and DK involved in data analysis and critical reading of the manuscript; KW, OK, and KB performed experiments; BB, KK, and AK did data collection; SZ and SSI performed manuscript review and editing, project administration; TI, RG, CB, and DJ performed manuscript review and editing; AZ contributed to project supervision, project administration, funding acquisition, resources, manuscript review, editing, and final approval.
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Raikwar, S.P., Thangavel, R., Ahmed, M.E. et al. Real-Time Noninvasive Bioluminescence, Ultrasound and Photoacoustic Imaging in NFκB-RE-Luc Transgenic Mice Reveal Glia Maturation Factor-Mediated Immediate and Sustained Spatio-Temporal Activation of NFκB Signaling Post-Traumatic Brain Injury in a Gender-Specific Manner. Cell Mol Neurobiol 41, 1687–1706 (2021). https://doi.org/10.1007/s10571-020-00937-9
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DOI: https://doi.org/10.1007/s10571-020-00937-9