MATRIX METALLOPROTEINASE AND APOPTOSIS IN BRAIN TRAUMA

Summary

Principal Investigator: ENG LO
Abstract: DESCRIPTION: (Verbatim from the Applicant's Abstract) In this proposal, we will use a mouse model of controlled cortical impact to test the idea that secondary cell death after traumatic brain injury is mediated by matrix metalloproteinases (MMP) which disrupt cell-matrix and cell-cell interactions, thus triggering apoptosis in brain regions beyond the site of original impact. Our working hypothesis states that: 1) mechanical stress induced by trauma activate MAP kinase signal transduction pathways, 2) MAP kinease pathways upregulate MMP expression, 3) MMP disrupts the extracellular matrix, and 4) disruption of cell-matrix and cell-cell interactions lead to apoptotic cell death. Preliminary data show that (a) the mouse model of controlled cortical impact is stable and reproducible in our lab; (b) western blots from traumatized brain show activation of the MAP kinase pathways ERK and SAPK2/p38; (c) the ERK/MAP kinase pathway upregulates MMP in vitro; (d) MMP activation occurs after trauma in vivo; (e) knockout mice deficient in MMP-9 show reduced injury after stroke and trauma, (f) direct injection of MMP-7 into mouse brain induces apoptosis; and (g) inhibition of the ERK/MAP kinase pathway reduces injury after stroke. We will extend our preliminary findings by pursuing the following specific aims. 1. Define the signaling pathways that lead to MMP upregulation and apoptosis after trauma. MMP gene promoter regions contain AP1 sites. Therefore, we propose that upstream activators of MMP involve MAP kinase signal transduction pathways. We will map the regional and temporal profiles of three major MAP kinsaes after trauma: ERK, SAPK1/JNK, and SAPK2/p38. Correlations between MAP kinase pathways, MMP expression , matrix disruption and apoptotic cell death will be assessed. 2. Characterize the role of specific MMP after trauma. We will examine morphological, biochemical and behavioral responses to trauma in MMP-2, MMP-7 and MMP-9 knockout mice, and transgenic mice overexpressing tissue inhibitor of MMP (TIMP-1). 3. Test the Neuroprotective effects of inhibitors of the ERK pathway (PD98059, U0216), p38 pathway (SB203580) and MMP (BB-94) for traumatic brain injury. Both morphological and behavioral outcomes will be measured. To date, there are not effective treatments for traumatic brain injury. Results from these proposed experiments will help identify MMP and upstream MAP kinase pathways as viable therapeutic targets for this devastating condition.
Funding Period: 2000-07-06 - 2005-06-30
more information: NIH RePORT

Top Publications

  1. pmc Vascular endothelial growth factor regulates the migration of oligodendrocyte precursor cells
    Kazuhide Hayakawa
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neurosci 31:10666-70. 2011
  2. ncbi Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study
    Peter J Kelly
    Neurovascular Clinical Science Unit, Mater University Hospital and University College Dublin, Ireland
    Stroke 39:100-4. 2008
  3. pmc Reduction of hippocampal cell death and proteolytic responses in tissue plasminogen activator knockout mice after transient global cerebral ischemia
    S R Lee
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
    Neuroscience 150:50-7. 2007
  4. ncbi Cell-cell signaling in the neurovascular unit
    Josephine Lok
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, MGH East 149 2401, Charlestown, MA 02129, USA
    Neurochem Res 32:2032-45. 2007
  5. ncbi TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice
    Daniela Bermpohl
    Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
    J Cereb Blood Flow Metab 27:1806-18. 2007
  6. ncbi Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke
    Bing Qiao Zhao
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Stroke 38:748-52. 2007
  7. ncbi Effects of apoE isoforms on beta-amyloid-induced matrix metalloproteinase-9 in rat astrocytes
    Shuzhen Guo
    Department of Neurology, Mass General Hospital, Charlestown, MA, USA
    Brain Res 1111:222-6. 2006
  8. ncbi Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage
    Emiri Tejima
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA
    J Cereb Blood Flow Metab 27:460-8. 2007
  9. ncbi Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke
    M Ning
    Stroke Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
    Neurology 66:1550-5. 2006
  10. ncbi Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke
    Seong Ryong Lee
    Department of Neurology and Radiology, Massachusetts General Hospital, Boston, Massachusetts 02129, USA
    J Neurosci 26:3491-5. 2006

Scientific Experts

  • Klaus van Leyen
  • Aneesh Singhal
  • Peter J Kelly
  • Eng H Lo
  • Bing Qiao Zhao
  • Shuzhen Guo
  • Emiri Tejima
  • Xiaoying Wang
  • Kiyoshi Tsuji
  • Kazuhide Hayakawa
  • Ken Arai
  • Josephine Lok
  • Michael J Whalen
  • Daniela Bermpohl
  • S R Lee
  • Woo Jean Kim
  • E H Lo
  • X Wang
  • M Ning
  • Seong Ryong Lee
  • Sophia Wang
  • Joan Montaner
  • Hahn Young Kim
  • Sun Ryung Lee
  • Wellington Pham
  • Loc Duyen D Pham
  • Angel T Som
  • Brian J Lee
  • Zerong You
  • H Y Kim
  • Y Murata
  • P L Huang
  • M A Moskowitz
  • Punkaj Gupta
  • A Rosell
  • Hyung Hwan Kim
  • R Gilberto Gonzalez
  • J Lok
  • C Ayata
  • Anna Rosell
  • D Atochin
  • David J Mooney
  • Brian J Bacskai
  • A G Sorensen
  • Pradeep Bhide
  • Hannah Storrie
  • Bruce R Rosen
  • Matthew P Frosch
  • M Zhu
  • Steven M Greenberg
  • M Barron
  • K L Furie
  • M Lederer
  • W J Koroshetz
  • H Lee
  • Jack M Parent
  • Jadwiga Rogowska
  • Bruce Rosen
  • Toshiaki Aoki
  • Paul L Huang
  • Anna Moore
  • Zdravka Medarova
  • Dmitriy N Atochin

Detail Information

Publications16

  1. pmc Vascular endothelial growth factor regulates the migration of oligodendrocyte precursor cells
    Kazuhide Hayakawa
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neurosci 31:10666-70. 2011
    ..Our findings demonstrate that VEGF-A can induce OPC migration via an ROS- and FAK-dependent mechanism, and suggest a novel role for VEGF-A in white-matter maintenance and homeostasis...
  2. ncbi Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study
    Peter J Kelly
    Neurovascular Clinical Science Unit, Mater University Hospital and University College Dublin, Ireland
    Stroke 39:100-4. 2008
    ..We aimed to determine the change in plasma F2IP levels over time and relationship with plasma MMP-9 in tPA-treated and tPA-untreated stroke patients...
  3. pmc Reduction of hippocampal cell death and proteolytic responses in tissue plasminogen activator knockout mice after transient global cerebral ischemia
    S R Lee
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
    Neuroscience 150:50-7. 2007
    ..Taken together, these data suggest that endogenous tPA contributes to hippocampal injury after cerebral ischemia, and these pathophysiologic pathways may involve links to aberrant activation of caspases and MMPs...
  4. ncbi Cell-cell signaling in the neurovascular unit
    Josephine Lok
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, MGH East 149 2401, Charlestown, MA 02129, USA
    Neurochem Res 32:2032-45. 2007
    ....
  5. ncbi TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice
    Daniela Bermpohl
    Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
    J Cereb Blood Flow Metab 27:1806-18. 2007
    ....
  6. ncbi Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke
    Bing Qiao Zhao
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Stroke 38:748-52. 2007
    ..Acute versus chronic protease profiles within the neurovascular unit are likely to underlie critical responses to stroke, therapy, and recovery...
  7. ncbi Effects of apoE isoforms on beta-amyloid-induced matrix metalloproteinase-9 in rat astrocytes
    Shuzhen Guo
    Department of Neurology, Mass General Hospital, Charlestown, MA, USA
    Brain Res 1111:222-6. 2006
    ..Reduction of astrocytic MMP-9 by apoE4 may affect Abeta clearance and promote Abeta deposition in AD...
  8. ncbi Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage
    Emiri Tejima
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA
    J Cereb Blood Flow Metab 27:460-8. 2007
    ....
  9. ncbi Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke
    M Ning
    Stroke Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
    Neurology 66:1550-5. 2006
    ..The authors investigated plasma MMP9 and its endogenous inhibitor, tissue inhibitor of metalloproteinase (TIMP1), in tPA-treated and -untreated stroke patients...
  10. ncbi Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke
    Seong Ryong Lee
    Department of Neurology and Radiology, Massachusetts General Hospital, Boston, Massachusetts 02129, USA
    J Neurosci 26:3491-5. 2006
    ..These data suggest that MMPs are involved in endogenous mechanisms of neurogenic migration as the brain seeks to heal itself after injury...
  11. ncbi Role of matrix metalloproteinases in delayed cortical responses after stroke
    Bing Qiao Zhao
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, MGH East 149 2401, Charlestown, Massachusetts 02129, USA
    Nat Med 12:441-5. 2006
    ..These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery...
  12. ncbi Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia
    Kiyoshi Tsuji
    Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
    Stroke 36:1954-9. 2005
    ..Here, we used a combination of pharmacological and genetic approaches to show that tPA promotes MMP-9 levels in stroke in vivo...
  13. ncbi Crossing the blood-brain barrier: a potential application of myristoylated polyarginine for in vivo neuroimaging
    Wellington Pham
    MGH MIT HMS Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, USA
    Neuroimage 28:287-92. 2005
    ..We conclude that this approach can be used for the delivery of imaging probes and potentially targeted therapeutics across the BBB...
  14. ncbi A pilot study of normobaric oxygen therapy in acute ischemic stroke
    Aneesh B Singhal
    Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass 02114, USA
    Stroke 36:797-802. 2005
    ..Therapies that transiently prevent ischemic neuronal death can potentially extend therapeutic time windows for stroke thrombolysis. We conducted a pilot study to investigate the effects of high-flow oxygen in acute ischemic stroke...
  15. pmc Proteasome inhibition protects HT22 neuronal cells from oxidative glutamate toxicity
    Klaus van Leyen
    Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
    J Neurochem 92:824-30. 2005
    ..These findings suggest that caspases can be decoupled from oxidative stress under some conditions, and implicate the ubiquitin/proteasome pathway in neuronal cell death caused by oxidative glutamate toxicity...