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Impact of Traumatic Brain Injury on Kallikrein 6

Title: Impact of Traumatic Brain Injury on Kallikrein 6.
Name(s): Phipps, Helen Wilma, author
Blaber, Michael, professor directing dissertation
Hyson, Richard L., university representative
Levenson, Cathy, committee member
Nowakowski, Richard, committee member
VanLandingham, Jacob, committee member
College of Medicine, degree granting department
Florida State University, degree granting institution
Type of Resource: text
Genre: Text
Issuance: monographic
Date Issued: 2013
Publisher: Florida State University
Place of Publication: Tallahassee, Florida
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: The secondary injury cascades in the acute phase of traumatic brain injury (TBI) are often the most devastating to patient outcome. These cascades include the neurobiological and neurochemical changes subsequent to the mechanical trauma inflicted whether direct, or indirect. Major secondary events include edema and inflammation, both leading to increased cell damage, demyelination, and cell death. Such secondary cascades alter blood flow, concentrations of ions, metabolism, and structural integrity ultimately leading to deteriorating patient outcome days after the injury rather than immediately. Many studies examine individual aspects of the secondary mechanisms to find potential biomarkers and/or therapeutic targets for TBI. However, no effort has proven successful at identifying a single biomarker of diagnostic or therapeutic application in part due to the heterogeneity of the condition – there remains a significant void in details about the secondary mechanisms of TBI that are still not understood. Ultimately the goal of this research is to better characterize the heterogeneous nature of TBI to allow for identification and inhibition of cell damage and death by inhibiting these secondary mechanisms. The kallikrein (human: KLK; rodent: Klk) family of serine proteases is one potential target that has not been examined with respect to TBI. Among the 15 known kallikreins (numbered 1–15), KLK6 is the most abundant in the brain and is associated with numerous aspects of the secondary TBI cascade. My primary goal is to identify a blood biomarker for diagnosing TBI and for tracking the efficacy of future drugs that prevent demyelination and cell death. To assist in this goal, the first aim of this study focused on analysis of the level of Klk6 in rodent brain and blood in three models of rat brain injury: mild (closed head), moderate (2.0 mm depth of impact), and severe (3.0 mm depth of impact). Protein assays determined levels of Klk6 at 3 and 24 h post–mild injury and 3, 6, 9, 24, 72, and 96 h post-moderate and severe injury and in sham and craniotomy-only operates. Comparison of Klk6 levels over time and across grades of injury severity are presented with respect to known substrates of Klk6 and to well-studied biomarkers of inflammatory demyelination characteristic of TBI to include: myelin basic protein (MBP) and tumor necrosis factor–α (TNFα). Immunohistochemistry determined the extent of corresponding pathology. These data supports Klk6 as a potentially important new physiological biomarker of TBI worthy of additional future study. The second aim of this study focused on analysis of the effect of neurosteroid treatment on Klk6 levels in brain and blood after severe TBI and the corresponding levels of inflammatory demyelination. Here, the indirect effect of allopregnanolone (ALLO) – an existing treatment of TBI in rodent studies which is known to increase the levels of free serpin in the brain – on Klk6 is described with respect to pathological implications. Protein assays determined reduced levels of Klk6 overall and specifically at 3, 6, and 9 h, but not at 24 h post–severe injury as compared to untreated. Immunohistochemistry determined corresponding alterations in pathology as a result of treatment with ALLO and suggest demyelination and inflammation are not significantly altered within 9 h of treatment with ALLO despite a reduction in the overall levels of Klk6. Additional studies beyond this time point are not warranted at this time due to the reductions in Klk6 by 24 h in untreated controls. However, further studies are warranted to examine the specific mechanism by which the Klk6 is reduced. Overall, the results support the hypothesis that Klk6 is involved in the secondary mechanisms of TBI and serum levels are a discrete diagnostic biomarker in rodents. Furthermore, treatment of injured rodents with ALLO decreases Klk6 acutely. However, reductions in Klk6 within 24 h were not paired with comparable improvements in inflammation or demyelination suggesting that the improvements require more than 24 h whether due to a delayed increase in serpins or by delayed remyelination potentially due to sustained inflammation. Therefore, although Klk6 appears to be a promising diagnostic biomarker, it does not appear to be a promising acute therapeutic biomarker of secondary pathology recovery.
Identifier: FSU_migr_etd-7550 (IID)
Submitted Note: A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Degree Awarded: Summer Semester, 2013.
Date of Defense: May 13, 2013.
Keywords: concussion, cortical impact, demyelination, inflammation, neurosteroids, protease
Bibliography Note: Includes bibliographical references.
Advisory Committee: Michael Blaber, Professor Directing Dissertation; Richard L. Hyson, University Representative; Cathy Levenson, Committee Member; Richard Nowakowski, Committee Member; Jacob VanLandingham, Committee Member.
Subject(s): Medicine
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Owner Institution: FSU

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Phipps, H. W. (2013). Impact of Traumatic Brain Injury on Kallikrein 6. Retrieved from