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UNIVERSITY of CALIFORNIA Los Angeles Characterizing UNIVERSITY OF CALIFORNIA Los Angeles Characterizing Neurotrauma and Astroglial Injury Biomarkers by Proteomics and Mass Spectrometry A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biochemistry and Molecular Biology by Sean Shen 2016 © Copyright by Sean Shen 2016 ABSTRACT OF THE DISSERTATION Characterizing Neurotrauma and Astroglial Injury Biomarkers by Proteomics and Mass Spectrometry by Sean Shen Doctor of Philosophy in Biochemistry and Molecular Biology University of California, Los Angeles, 2016 Professor Joseph Ambrose Loo, Chair Neurotraumatic injury has long been a leading cause of death and disability worldwide. Recently, the debilitating long term effects of chronic, mild traumatic brain injuries (TBIs) have gained increased public attention. In order to protect individuals most at risk (e.g. military personnel and athletes) from such injuries, improved diagnostics in the form of a biomarker panel capable of rapidly and sensitively detecting mild TBIs are needed. Despite the large number of TBI biomarker studies in the literature, the development of a clinically relevant protein signature remains elusive. In contrast to diseases with singular mechanistic dysfunction, neurotrauma is characterized by the disruption to multiple cellular pathways that contribute to the sequelae of secondary pathophysiology that determines patient outcome and recovery. This complexity has been a confounding factor in the identification of effective biomarkers. In an effort to circumvent this hurdle, our group implemented a central nervous system ii (CNS) specific cell injury model to examine preferentially released injury related proteins as candidate diagnostics. Comparative analysis of a TBI CSF proteome and preferentially released proteins from our injury model revealed a panel of astroglial injury related candidate biomarkers including aldolase C (ALDOC), brain lipid binding protein (BLBP), glutamine synthetase (GS), astrocytic phosphoprotein PEA15 (PEA15), and glial fibrillary acidic protein (GFAP) and its trauma-generated breakdown products (BDPs). Immediate and robust release of ALDOC, BLBP, and PEA15 were associated more with acute cell wounding than cell death observed after biomechanical injury. In contrast, GFAP release correlated primarily with cell death. The sensitivity and selectivity of our biomarkers for neurotrauma were evaluated in human TBI and Yucatan swine spinal cord injury (SCI) CSF samples. Verification studies demonstrated the ability of our astroglial biomarker panel to differentiate injury from non-injury with elevated signals detectable an hour after injury. Additionally, differential CSF concentration kinetics were observed over a 1-week period post-injury indicative of a long diagnostic window. CSF concentration of biomarkers GFAP, ALDOC, and BLBP correlated strongly with the extent of tissue loss after SCI at 7 days. Taken together, our data demonstrates the successful application of proteomics to the identification and verification of new neurotrauma biomarkers that exhibit potential for not only detecting but defining injury severity. iii This dissertation of Sean Shen is approved. Gal Bitan Jorge Torres Joseph Ambrose Loo, Committee Chair University of California, Los Angeles 2016 iv TABLE OF CONTENTS CHAPTER 1: TRAUMATIC BRAIN INJURY – CLINICAL AND MOLECULAR PATHOLOGIES .............................................................................................................. 1 1.1 INTRODUCTION ................................................................................................... 1 1.2 CLASSIFICATON OF TRAUMATIC BRAIN INJURY ............................................. 3 1.3 CLINICAL PATHOLOGIES OF NEUROTRAUMA ................................................. 6 1.4 THE MOLECULAR PATHOPHYSIOLOGY OF NEUROTRAUMA ....................... 10 1.5 CONCLUSION ..................................................................................................... 18 1.6 REFERENCES .................................................................................................... 20 CHAPTER 2: ADDRESSING THE NEEDS OF TRAUMATIC BRAIN INJURY WITH CLINICAL PROTEOMICS ........................................................................................... 30 2.1 INTRODUCTION ................................................................................................ 30 2.2 DISCUSSION ....................................................................................................... 32 2.3 CONCLUSIONS ................................................................................................. 53 2.4 FIGURES ............................................................................................................. 54 2.5 TABLES ............................................................................................................... 55 2.6 REFERENCES ................................................................................................... 56 CHAPTER 3: NEW ASTROGLIAL INJURY DEFINED BIOMARKERS FOR NEUROTRAUMA ASSESSMENT ................................................................................. 78 3.1 INTRODUCTION ................................................................................................. 78 3.2 RESULTS ............................................................................................................ 81 2.3 DISCUSSION ....................................................................................................... 93 3.4 METHODS ......................................................................................................... 102 2.5 FIGURES ........................................................................................................... 112 3.6 TABLES ............................................................................................................. 129 3.7 SUPPLEMENTAL FIGURES ............................................................................. 158 3.8 REFERENCES .................................................................................................. 174 CHAPTER 4: ASSESSMENT OF ASTROGLIAL INJURY DEFINED BIOMARKERS IN SPINAL CORD INJURY .............................................................................................. 198 4.1 INTRODUCTION ............................................................................................... 198 4.2 RESULTS .......................................................................................................... 201 4.3 DISCUSSION ..................................................................................................... 207 v 4.4 METHODS ......................................................................................................... 209 4.5 FIGURES ........................................................................................................... 213 4.6 TABLES ............................................................................................................. 233 4.7 REFERENCES .................................................................................................. 239 CHAPTER 5: CHARACTERIZING THE PREFERENTIAL RELEASE OF PROTEIN SUBPOPULATIONS BY INJURED ASTROCYTES .................................................... 243 5.1 INTRODUCTION ............................................................................................... 243 5.2 RESULTS .......................................................................................................... 245 5.3 DISCUSSION ..................................................................................................... 250 5.4 METHODS ......................................................................................................... 255 5.5 FIGURES ........................................................................................................... 259 5.6 TABLES ............................................................................................................. 269 5.7 REFERENCES .................................................................................................. 312 CHAPTER 6: FUTURE DIRECTIONS FOR SPINAL CORD AND HEAD TRAUMA ... 320 6.1 INTRODUCTION ............................................................................................... 320 6.2 RESULTS .......................................................................................................... 321 6.3 DISCUSSION ..................................................................................................... 325 6.4 CONCLUDING REMARKS ................................................................................ 328 6.5 METHODS ......................................................................................................... 333 6.6 FIGURES ........................................................................................................... 335 6.7 TABLES ............................................................................................................. 337 6.8 REFERENCES .................................................................................................. 352 vi LIST OF FIGURES AND TABLES Figure 2.1: ..................................................................................................................... 54 Table 2.1: ...................................................................................................................... 55 Figure 3.1: ..................................................................................................................
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