Integration of Proteomics, Bioinformatics, and Systems Biology in Traumatic Brain Injury Biomarker Discovery

Abstract

Traumatic brain injury (TBI) is a major medical crisis without any FDA-approved pharmacological therapies that have been demonstrated to improve functional outcomes. It has been argued that discovery of disease-relevant biomarkers might help to guide successful clinical trials forTBI. Major advances in mass spectrometry (MS) have revolutionized the field of proteomic biomarker discovery and facilitated the identification of several candidate markers that are being further evaluated for their efficacy asTBI biomarkers. However, several hurdles have to be overcome even during the discovery phase which is only the first step in the long process of biomarker development. The high-throughput nature of MS-based proteomic experiments generates a massive amount of mass spectral data presenting great challenges in downstream interpretation. Currently, different bioinformatics platforms are available for functional analysis and data mining of MS-generated proteomic data. These tools provide a way to convert data sets to biologically interpretable results and functional outcomes. A strategy that has promise in advancing biomarker development involves the triad of proteomics, bioinformatics, and systems biology. In this review, a brief overview of how bioinformatics and systems biology tools analyze, transform, and interpret complex MS datasets into biologically relevant results is discussed. In addition, challenges and limitations of proteomics, bioinformatics, and systems biology in TBI biomarker discovery are presented. A brief survey of researches that utilized these three overlapping disciplines in TBI biomarker discovery is also presented. Finally, examples of TBI biomarkers and their applications are discussed.

Blood biomarkers for evaluation of perinatal encephalopathy: state of the art

“…One of the main strengths of GFAP as a brain injury biomarker is that it is only found within the central nervous system (CNS; Galea et al, 1995). GFAP is a cytoskeletal intermediate filament protein that forms networks that support astroglial cells and is found only in the astroglial cytoskeleton (Guingab-Cagmat et al, 2013). Astrocytes are important to brain injury because their foot processes comprise part of the blood brain barrier, and with disruption after injury astrocyte damage results in early release of GFAP (Vos et al, 2004;Guingab-Cagmat et al, 2013).…”

“…Of the numerous candidate biomarkers for traumatic brain injury GFAP holds the most promise (Guingab-Cagmat et al, 2013). One of the main strengths of GFAP as a brain injury biomarker is that it is only found within the central nervous system (CNS; Galea et al, 1995).…”

“…In premature infants in particular, the blood brain barrier is particularly fragile, potentially increasing the likelihood that brain proteins may reach the circulation after injury (Dammann and Leviton, 1997). Clearance and half-life of the biomarkers contribute to the final concentration that can be measured in blood (Guingab-Cagmat et al, 2013). Review of recent research in traumatic brain injury suggests significant potential for crossover of traumatic brain injury biomarkers to the brain injured fetus and neonate.…”

“…In the discovery driven method samples from normal and brain injured patients are compared with mass spectrometry to identify differences in circulating brain proteins. Unlike hypothesis driven research that identifies potential biomarkers before testing them in cases and controls, discovery driven research collects a huge amount of information first then extracts questions and answers from the data (Guingab-Cagmat et al, 2013). As currently there is no gold standard for diagnosing mild traumatic brain injury, not even by conventional assessment through neuroimaging techniques, (Niogi and Mukherjee, 2010) these approaches have been applied to identify brain specific markers of injury.…”

“…As currently there is no gold standard for diagnosing mild traumatic brain injury, not even by conventional assessment through neuroimaging techniques, (Niogi and Mukherjee, 2010) these approaches have been applied to identify brain specific markers of injury. During brain injury, neural proteins or their breakdown products are released into the extracellular environment reaching the cerebrospinal fluid (CSF) in relatively high concentration, and the blood stream via the compromised blood-brain barrier (Guingab-Cagmat et al, 2013; Figure 1). In premature infants in particular, the blood brain barrier is particularly fragile, potentially increasing the likelihood that brain proteins may reach the circulation after injury (Dammann and Leviton, 1997).…”