Proteomics: in pursuit of effective traumatic brain injury therapeutics

Abstract

Effective traumatic brain injury (TBI) therapeutics remains 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 because 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. Finally, 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 patients with TBI.

Keywords:

• brain injury
• informatics
• inhibitory synapses
• post-translational modification
• proteomics
• TBI
• temporal
• theragnostics
• therapeutics

Acknowledgements

The authors thank P De Domenico of the University of Messina, Italy, for assisting with microscopy data collection.

Financial & competing interests disclosure

This work was supported in part by the National Institutes of Health grant NS055012 and Virginia Commonwealth School of Medicine. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Despite growing public recognition and increased research attention, advances in traumatic brain injury (TBI) therapeutics have failed to materialize.

• Large-scale proteomics offers a forward leap in our capacity to study the molecular impact of candidate drugs, both positive and negative, and how their action can be tailored across injury and population factors that give rise to the heterogeneity of clinical TBI.

• Temporal characteristics of the neuroproteomic response to TBI are critical to understanding the sequential nature of the molecular processes governing secondary insults, recovery and regeneration.

• Accounting for the breadth of translational and post-translational proteomic responses to TBI represents a monumental big-data challenge, requiring improved molecular characterization and informatic technologies.

• Objective biofluid measures of ongoing biochemical change are needed to assist translation of novel therapeutics. Theragnostic assays are needed for subject selection and as objective outcome measures in future clinical trials.

Notes