The injured spinal cord is exposed to early barrier disruption and inflammation as well as complex repair processes that collectively define an environmental terrain that influences axonal plasticity and governs the extent of functional recovery. This proposal examines the dual roles of matrix metalloproteinases (MMPs), a family of proteolytic enzymes, in promoting both early tissue damage and fostering wound healing in the injured spinal cord. We will focus on a class of MMPs, the gelatinases, which are expressed in the spinal cord and are upregulated in response to spinal cord injury. MMP-9/gelatinase B is dramatically increased in the acutely injured cord and promotes disruption of the blood-spinal cord barrier and neutrophil infiltration. We hypothesize that MMP-9, produced by infiltrating leukocytes, disrupts the barrier and promotes early inflammation by degrading substrates critical to the integrity of the barrier and by inactivating alpha1-protease inhibitor, the inhibitor to neutrophil elastase. The end results are transient barrier dysfunction and tissue damage, resulting in part from the uncontrolled proteolytic activity of neutrophil elastase. MMP-2/gelatinase A, unlike MMP-9, is not actively expressed in the acutely injury spinal cord. Rather, MMP-2 activity is most prominent between 7 and 14 days post injury, a period corresponding to revascularization and glial scar formation. We hypothesize that MMP-2 modulates angiogenesis and glial scar formation and thus defines an environment that influences both axonal plasticity and functional recovery. To test these hypotheses, we will use a reproducible model of spinal cord contusion injury and several strategies for modulating MMP and neutrophil elastase activity. We will compare barrier permeability and inflammation in spinal cord injured mice with null mutations in MMP-9 and neutrophil elastase to injured mice that express these proteases. Reconstitution studies will be used to determine the extent to which MMP-9 expressing leukocytes disrupt the barrier, infiltrate the cord, and promote early tissue damage. /n vivo studies and in vitro bioassays will be used to compare wound healing including angiogenesis, glial scar formation, and axonal sparing/plasticity in spinal cord injured MMP-2 null mice and wildtype littermates.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CNNT (01))
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Kleitman, Naomi
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Trivedi, Alpa; Zhang, Haoqian; Ekeledo, Adanma et al. (2016) Deficiency in matrix metalloproteinase-2 results in long-term vascular instability and regression in the injured mouse spinal cord. Exp Neurol 284:50-62
Levine, Jonathan M; Cohen, Noah D; Heller, Michael et al. (2014) Efficacy of a metalloproteinase inhibitor in spinal cord injured dogs. PLoS One 9:e96408
Phillips, Joanna J; Huillard, Emmanuelle; Robinson, Aaron E et al. (2012) Heparan sulfate sulfatase SULF2 regulates PDGFR? signaling and growth in human and mouse malignant glioma. J Clin Invest 122:911-22
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
Levine, Jonathan M; Levine, Gwendolyn J; Porter, Brian F et al. (2011) Naturally occurring disk herniation in dogs: an opportunity for pre-clinical spinal cord injury research. J Neurotrauma 28:675-88
Lee, Sang Mi; Rosen, Steven; Weinstein, Philip et al. (2011) Prevention of both neutrophil and monocyte recruitment promotes recovery after spinal cord injury. J Neurotrauma 28:1893-907
Zhang, Haoqian; Trivedi, Alpa; Lee, Jung-Uek et al. (2011) Matrix metalloproteinase-9 and stromal cell-derived factor-1 act synergistically to support migration of blood-borne monocytes into the injured spinal cord. J Neurosci 31:15894-903
Zhang, Haoqian; Adwanikar, Hita; Werb, Zena et al. (2010) Matrix metalloproteinases and neurotrauma: evolving roles in injury and reparative processes. Neuroscientist 16:156-70
Pozniak, Christine D; Langseth, Abraham J; Dijkgraaf, Gerrit J P et al. (2010) Sox10 directs neural stem cells toward the oligodendrocyte lineage by decreasing Suppressor of Fused expression. Proc Natl Acad Sci U S A 107:21795-800
Hsu, Jung-Yu C; Bourguignon, Lilly Y W; Adams, Christen M et al. (2008) Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord. J Neurosci 28:13467-77

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