Proteomics: in pursuit of effective traumatic brain injury therapeutics

Abstract

Summary Effective traumatic brain injury (TBI) therapeutics remain stubbornly elusive. Efforts in the field have been challenged by the heterogeneity of clinical TBI, with greater complexity among underlying molecular phenotypes than initially conceived. Future research must confront the multitude of factors comprising this heterogeneity, representing a big data challenge befitting the coming informatics age. Proteomics is poised to serve a central role in prescriptive therapeutic development, as it offers an efficient endpoint within which to assess post-TBI biochemistry. We examine rationale for multifactor TBI proteomic studies and the particular importance of temporal profiling in defining biochemical sequences and guiding therapeutic development. Lastly, we offer perspective on repurposing biofluid proteomics to develop theragnostic assays with which to prescribe, monitor and assess pharmaceutics for improved translation and outcome for TBI patients.

Influence of white matter injury on gray matter reactive gliosis upon stab wound in the adult murine cerebral cortex

“…This was for example the case for proteins involved in wound closure or fibrinolysis as well as several serine protease inhibitor proteins of the serpin family and the translocase of the outer mitochondrial membrane protein 70 homolog (TOM70A) that were detected previously (Mehan & Strauss, 2012) and also upregulated at the GM lesion side in both our injury conditions. Moreover, reduced synaptic proteins, changes in many GABAB receptors, chloride transporters, along with a reduction in Parvalbumin (see e.g., (Lizhnyak & Ottens, 2015) were also obvious in our proteome analysis.…”

“…The differential proliferative reaction of NG2 glia and astrocytes in the GM2 and GM1 injury conditions was not an isolated phenomenon, but rather coincided with the large proteome differences between these lesion conditions. While we were mostly interested in the differences between GM1 and GM2 injury, it was reassuring to see not only individual proteins regulated as expected, such as GFAP and Vimentin higher in both injury conditions compared with the respective contralateral sites, but also common pathways and proteins as observed in proteome analysis of other models of TBI (Boutte et al, 2012;Harish et al, 2015;Hsieh et al, 2016;Lizhnyak & Ottens, 2015;Mehan & Strauss, 2012). This was for example the case for proteins involved in wound closure or fibrinolysis as well as several serine protease inhibitor proteins of the serpin family and the translocase of the outer mitochondrial membrane protein 70 homolog (TOM70A) that were detected previously (Mehan & Strauss, 2012) and also upregulated at the GM lesion side in both our injury conditions.…”

Development of a systems‐based in situ multiplex biomarker screening approach for the assessment of immunopathology and neural tissue plasticity in male rats after traumatic brain injury

“…The restricted success of such a massive research investment demands a reevaluation of the pathobiology of evolving brain injury and a subsequent adjustment of experimental and therapeutic approaches (Dash et al 2010; Liu et al 2010; Lizhnyak and Ottens 2015). …”

“…Therapeutic interventions in animal models aimed at modulating major molecular pathways induced after TBI have limited the extent of injury and improved neurological recovery in the laboratory, yet all phase III clinical trials of these therapies in patients have failed to demonstrate efficacy. The restricted success of such a massive research investment demands a reevaluation of the pathobiology of evolving brain injury and a subsequent adjustment of experimental and therapeutic approaches (Dash, Zhao, Hergenroeder, & Moore, 2010;Liu et al, 2010;Lizhnyak & Ottens, 2015).…”

Neuroproteomics and Systems Biology Approach to Identify Temporal Biomarker Changes Post Experimental Traumatic Brain Injury in Rats

“…Of the proteins that are altered at 1 day post-CCI only are vinculin and protein-disulfide isomerase (Table 2A). Vinculin, an integrin complexing protein known to be associated with synaptic destabilization and process retraction, has been shown to dissociate from cellular membranes following TBI (87). It usually participates in anchoring actin filaments to the cell membrane and plays a crucial role in cell motility.…”