Traumatic and ischemic brain injury (TBI) represents a major CNS disorder without any clinically proven therapy. On one hand, various pharmaceutical agents have been shown to have beneficial effects in animal models of TBI. On the other hand, in the past 10 years, we have witnessed numerous failures in clinical drug trials for the treatment of TBI. This points to the difficulty of translating promising preclinical data into clinical successes. In retrospect, one key missing component in these clinical trails was the availability of robust clinical biomarkers that strongly correlate with disease severity, time course of disease progression and drug response. Our laboratory has pioneered the use of damaged cytoskeletal proteins as markers for acute brain injury. For example, we have shown that ?II-spectrin breakdown products (SBDPs) are prototypic protein markers for TBI since they meet two criteria: (1) index of structural injury and (2) Information on injury mechanism. Our experience in SBDPs had leaded us to use proteomic technologies to elucidate the currently poorly understood or protein pathways and biochemical mechanisms underlying TBI and to identify additional markers for TBI. With the recent technological advances in proteomics and the availability of the human proteome database, we predict that disease marker research will be a uniquely productive application of proteomic technologies. Using proteomic data to understand disease mechanism, protein-protein interactions or biochemical pathways is a daunting task. On the other hand, proteomic methods can be readily used to identify unique markers specific to a disease process such as TBI. Once novel markers are identified, sensitive detection tools (such as ELISA assays) can be developed for their detection in affected brain tissue, CSF and blood samples. Every proteomic technology has strengths and weaknesses and therefore they should be used concurrently. Thus, we are employing an integrated proteomics-based approach to discover novel biomarkers for TBI. We will be presenting data on these approaches: (1) 2D-gel electrophoresis-MALDI-TOF, (2) 2D-liquid chromatography (LC)-MALDI-TOF and MS/MS and (4) antibody panels and microarrays.
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