Trauma to Developing Brain-Injury and Repair Mechanisms

Summary

Principal Investigator: Linda J Noble
Abstract: DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) in children is the leading cause of death and disability. Although clinical studies have shown that the developing brain is particularly vulnerable to injury, the basis for this vulnerability remains unclear. Here we will determine if matrix metalloproteinase (MMP)-9 is a key initiator of early tissue damage and that modulation of its activity will confer early neuroprotection and establish an environment that is favorable to brain development and cognitive recovery. The gelatinase MMP-9 is a member of the MMP family of proteolytic enzymes that are secreted in an inactive form and are activated in the extracellular matrix (ECM) by a variety of mechanisms. While MMPs are critical for normal brain functioning, excessive and uncontrolled activity leads to dysregulated proteolysis, culminating in cell injury/death. Here we will determine if MMP-9 initiates an early self-perpetuating injury response that is coupled to activity of neutrophil elastase and neutrophil infiltration. We hypothesize that MMP-9 mediates early tissue damage by inactivating a1-protease inhibitor, the primary physiologic inhibitor of neutrophil elastase, thus supporting neutrophil elastase-mediated neuronal injury and furthering leukocyte recruitment. Using complimentary pharmacologic and genetic strategies, together with adoptive transfer, we will examine the cooperativity between MMP-9 and neutrophil elastase in signaling neutrophil recruitment and mediating early cell injury. Aim 1 will test the hypothesis that elevated MMP-9 contributes to disruption of the blood-brain barrier, neural injury, and white matter damage. Aim 2 will test the hypothesis that MMP-9, conveyed by infiltrating neutrophils, promotes disruption of the blood-brain barrier. Aim 3 will determine if MMP-9 inactivates a1-protease inhibitor, an inhibitor of neutrophil elastase, thus allowing neutrophil elastase to produce tissue injury and further neutrophil recruitment. Aim 4 will test the hypothesis that blockade of early gelatinase activity in the acutely injured brain will result in long-term structural and behavioral recovery. To test these hypotheses we will use a murine model of TBI at postnatal day 21 and several strategies to modulate MMP-9 and neutrophil elastase activity. We will compare early indices of tissue damage including barrier dysfunction in brain injured wildtype (WT) mice to transgenic mice with a null mutation in MMP-9 or overexpress tissue inhibitor of matrix metalloproteinase-1. The interdependency of MMP-9 and neutrophil elastase in initiating a self-perpetuating injury response will be examined using adoptive transfer techniques in WT and MMP-9 and neutrophil elastase null animals. With state-of-the-art magnetic resonance imaging and a comprehensive battery of behavioral assays, we will further determine if early pharmacologic blockage of gelatinase activity supports structural recovery and improves long-term cognitive outcomes. Together, these studies provide an important foundation for understanding the unique vulnerability of the young brain to TBI and for developing the most appropriate therapies for the brain-injured child.
Funding Period: 2004-12-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. pmc Traumatic injury to the immature brain: inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets
    Mathew B Potts
    Department of Neurological Surgery, University of California, San Francisco, 94143, USA
    NeuroRx 3:143-53. 2006
  2. pmc Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species
    Bridgette D Semple
    Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143 0112, USA
    Prog Neurobiol 106:1-16. 2013
  3. pmc Deficits in social behavior emerge during development after pediatric traumatic brain injury in mice
    Bridgette D Semple
    Department of Neurological Surgery, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143 0112, USA
    J Neurotrauma 29:2672-83. 2012
  4. pmc Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury
    Haoqian Zhang
    Department of Neurosurgery, University of California, San Francisco, California 94143 0110, USA
    Neurotherapeutics 8:206-20. 2011
  5. pmc Age is a determinant of leukocyte infiltration and loss of cortical volume after traumatic brain injury
    Catherine P Claus
    Department of Neurological Surgery, University of California, San Francisco, CA 94143 0112, USA
    Dev Neurosci 32:454-65. 2010
  6. pmc Matrix metalloproteinases and neurotrauma: evolving roles in injury and reparative processes
    Haoqian Zhang
    Department of Neurosurgery, University of California, San Francisco, CA 94143 0110, USA
    Neuroscientist 16:156-70. 2010
  7. pmc Heme oxygenase-2 modulates early pathogenesis after traumatic injury to the immature brain
    Tomoko Yoneyama-Sarnecky
    Department of Neurosurgery, University of California, San Francisco, Calif, USA
    Dev Neurosci 32:81-90. 2010
  8. pmc Finite element analysis of controlled cortical impact-induced cell loss
    Haojie Mao
    Bioengineering Center, Wayne State University, Detroit, Michigan 48201, USA
    J Neurotrauma 27:877-88. 2010
  9. pmc Traumatic brain injury: an overview of pathobiology with emphasis on military populations
    Ibolja Cernak
    National Security Technology Department, Johns Hopkins University Applied Physics Laboratory, Laurel, Maryland 20723, USA
    J Cereb Blood Flow Metab 30:255-66. 2010
  10. pmc Models of traumatic cerebellar injury
    Matthew B Potts
    Department of Neurological Surgery, University of California, Brain and Spinal Injury Center, San Francisco, CA 94143, USA
    Cerebellum 8:211-21. 2009

Detail Information

Publications16

  1. pmc Traumatic injury to the immature brain: inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets
    Mathew B Potts
    Department of Neurological Surgery, University of California, San Francisco, 94143, USA
    NeuroRx 3:143-53. 2006
    ..These processes thus provide potential therapeutic targets that may be tailored to pediatric TBI, including anti-inflammatory agents such as minocycline, antioxidants such as glutathione peroxidase, and the iron chelator deferoxamine...
  2. pmc Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species
    Bridgette D Semple
    Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143 0112, USA
    Prog Neurobiol 106:1-16. 2013
    ....
  3. pmc Deficits in social behavior emerge during development after pediatric traumatic brain injury in mice
    Bridgette D Semple
    Department of Neurological Surgery, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143 0112, USA
    J Neurotrauma 29:2672-83. 2012
    ..Thus, efficacy of therapeutics for pediatric TBI should take into account the time-dependent emergence of abnormal behavioral patterns...
  4. pmc Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury
    Haoqian Zhang
    Department of Neurosurgery, University of California, San Francisco, California 94143 0110, USA
    Neurotherapeutics 8:206-20. 2011
    ..Thus, we focus this review on the development of selective gelatinase inhibitors...
  5. pmc Age is a determinant of leukocyte infiltration and loss of cortical volume after traumatic brain injury
    Catherine P Claus
    Department of Neurological Surgery, University of California, San Francisco, CA 94143 0112, USA
    Dev Neurosci 32:454-65. 2010
    ..Together, these findings demonstrate age-dependent temporal patterns of leukocyte infiltration and loss of cortical volume after TBI...
  6. pmc Matrix metalloproteinases and neurotrauma: evolving roles in injury and reparative processes
    Haoqian Zhang
    Department of Neurosurgery, University of California, San Francisco, CA 94143 0110, USA
    Neuroscientist 16:156-70. 2010
    ....
  7. pmc Heme oxygenase-2 modulates early pathogenesis after traumatic injury to the immature brain
    Tomoko Yoneyama-Sarnecky
    Department of Neurosurgery, University of California, San Francisco, Calif, USA
    Dev Neurosci 32:81-90. 2010
    ..Together, these findings demonstrate that deficiency in HO-2 alters both the kinetics of secondary damage and fine motor recovery after TBI...
  8. pmc Finite element analysis of controlled cortical impact-induced cell loss
    Haojie Mao
    Bioengineering Center, Wayne State University, Detroit, Michigan 48201, USA
    J Neurotrauma 27:877-88. 2010
    ..More research is needed to examine other regions that do not have histological data for comparison with FE model predictions before this injury mechanism and the associated injury threshold can be fully established...
  9. pmc Traumatic brain injury: an overview of pathobiology with emphasis on military populations
    Ibolja Cernak
    National Security Technology Department, Johns Hopkins University Applied Physics Laboratory, Laurel, Maryland 20723, USA
    J Cereb Blood Flow Metab 30:255-66. 2010
    ....
  10. pmc Models of traumatic cerebellar injury
    Matthew B Potts
    Department of Neurological Surgery, University of California, Brain and Spinal Injury Center, San Francisco, CA 94143, USA
    Cerebellum 8:211-21. 2009
    ..Further research is needed to better understand the mechanisms underlying the pathogenesis of cerebellar trauma, and the experimental models discussed here offer an important first step toward achieving that objective...
  11. pmc Glutathione peroxidase activity modulates recovery in the injured immature brain
    Kyoko Tsuru-Aoyagi
    Department of Neurological Surgery, University of California San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143, USA
    Ann Neurol 65:540-9. 2009
    ..Here we consider glutathione peroxidase (GPx) activity as a determinant of recovery in the injured immature brain...
  12. pmc Glutathione peroxidase overexpression does not rescue impaired neurogenesis in the injured immature brain
    Matthew B Potts
    Brain and Spinal Injury Center and Department of Neurological Surgery, University of California, San Francisco, California, USA
    J Neurosci Res 87:1848-57. 2009
    ..087). Overall, these data demonstrate that traumatic injury to the injured immature brain impairs neurogenesis during maturation and suggest that GPx cannot rescue this reduced neurogenesis...
  13. ncbi Injury severity determines Purkinje cell loss and microglial activation in the cerebellum after cortical contusion injury
    Takuji Igarashi
    Department of Neurological Surgery, University of California, San Francisco, 521 Parnassus Avenue, Room C 224, San Francisco, CA 94143 0520, USA
    Exp Neurol 203:258-68. 2007
    ..That a selective pattern of Purkinje cell loss occurs regardless of the type of injury suggests a generalized response that is a likely determinant of recovery and a target for therapeutic intervention...
  14. ncbi Traumatic injury to the immature brain results in progressive neuronal loss, hyperactivity and delayed cognitive impairments
    Ramadevi Pullela
    Department of Pediatrics, University of California, San Francisco, CA 94143 0520, USA
    Dev Neurosci 28:396-409. 2006
    ..Behavioral changes are a likely consequence of regional-specific neuronal degeneration...
  15. ncbi Alterations in hippocampal neurogenesis following traumatic brain injury in mice
    Radoslaw Rola
    Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
    Exp Neurol 202:189-99. 2006
    ..No differences were noted in oligodendrocytes (BrdU/NG2). Taken together, these data demonstrate that TBI alters both neurogenesis and gliogenesis. Such alterations may play a contributory role in TBI-induced cognitive impairment...
  16. pmc Traumatic injury to the immature frontal lobe: a new murine model of long-term motor impairment in the absence of psychosocial or cognitive deficits
    Chien Yi Chen
    Department of Neurological Surgery, University of California, San Francisco, San Francisco, Calif, USA
    Dev Neurosci 35:474-90. 2013
    ....