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.

Public Health Relevance

Although traumatic brain injury (TBI) is the most frequent cause of acquired brain injury and morbidity in children and adversely impacts cognitive development, there has been little progress toward understanding how best to support recovery processes. Using genetic and pharmacologic approaches in a murine model of TBI, we will determine how unchecked, matrix metalloproteinase (MMP)-9 directed proteolysis establishes an environment that is unfavorable to recovery and if early blockade of this activity supports cognitive recovery. These studies establish the basis for developing a MMP-targeted therapeutic for the brain-injured child.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050159-08
Application #
8431806
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2004-12-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2013
Total Cost
$397,011
Indirect Cost
$118,333
Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Semple, Bridgette D; Noble-Haeusslein, Linda J; Jun Kwon, Yong et al. (2014) Sociosexual and communication deficits after traumatic injury to the developing murine brain. PLoS One 9:e103386
Semple, Bridgette D; Blomgren, Klas; Gimlin, Kayleen et al. (2013) Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol 106-107:1-16
Chen, Chien-Yi; Noble-Haeusslein, Linda J; Ferriero, Donna et al. (2013) Traumatic injury to the immature frontal lobe: a new murine model of long-term motor impairment in the absence of psychosocial or cognitive deficits. Dev Neurosci 35:474-90
Zhang, Haoqian; Chang, Mayland; Hansen, Christopher N et al. (2011) Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury. Neurotherapeutics 8:206-20
Mao, Haojie; Jin, Xin; Zhang, Liying et al. (2010) Finite element analysis of controlled cortical impact-induced cell loss. J Neurotrauma 27:877-88
Zhang, Haoqian; Adwanikar, Hita; Werb, Zena et al. (2010) Matrix metalloproteinases and neurotrauma: evolving roles in injury and reparative processes. Neuroscientist 16:156-70
Yoneyama-Sarnecky, Tomoko; Olivas, Andrea D; Azari, Soraya et al. (2010) Heme oxygenase-2 modulates early pathogenesis after traumatic injury to the immature brain. Dev Neurosci 32:81-90
Cernak, Ibolja; Noble-Haeusslein, Linda J (2010) Traumatic brain injury: an overview of pathobiology with emphasis on military populations. J Cereb Blood Flow Metab 30:255-66
Potts, Matthew B; Rola, Radoslaw; Claus, Catherine P et al. (2009) Glutathione peroxidase overexpression does not rescue impaired neurogenesis in the injured immature brain. J Neurosci Res 87:1848-57

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