White matter (WM) injury, which is characterized by axonal degeneration and loss of the myelin sheath (demyelination), is important for the long-term functional deficits after traumatic brain injury (TBI). The central nervous system exhibits limited capacity for WM repair, such as axonal regeneration and remyelination. During post-TBI WM repair, oligodendrocyte precursor cells (OPCs) are known to actively proliferate. However, many newly generated OPCs fail to differentiate into mature, myelin- This application will examine the effect of intranasal delivery of protease inactive plasminogen activator mutant (tPAm) to enhance differentiation and maturation of oligodendyocytes to promote white matter integrity following TBI. producing oligodendrocytes (OLs), resulting in inadequate remyelination. Failed remyelination not only diminishes signal transduction, but also leads to axon degeneration and worsens clinical outcome. Thus, interventions that promote OPC differentiation and maturation are promising strategies to enhance WM repair and improve functional recovery. Recombinant tissue plasminogen activator (tPA) is an FDA-approved treatment for ischemic stroke and catalyzes thrombolysis through serine protease action. Recent studies have discovered direct neurorestorative effects of tPA independent of protease activities. However, the clinical use of tPA as a therapeutic agent in TBI raises several concerns, as it can also cause blood-brain barrier damage and brain edema. In this proposal, we will explore protease-inactive mutant tPA (tPAm), with substitution of a single amino acid (S478A) to eliminate protease action, as a novel restorative therapy to promote remyelination and WM repair after TBI. We discovered that nanomolar concentrations of tPAm promote the differentiation of cultured primary OPCs into mature OLs. In addition, tPA knockout exacerbates behavioral deficits and WM injury lasting at least 35 days after TBI whereas post-injury intranasal administration of tPAm improves long-term neurological function and WM integrity after TBI in mice. Pilot data further suggest that tPAm enhances WM repair after TBI by promoting OPC differentiation and axon remyelination and that the effect may be mediated by the peroxisome proliferator-activated receptor ? (PPAR?) nuclear receptor. Here we will focus on the novel remyelinating actions of tPAm and test the following hypothesis: Treatment with protease inactive tPAm facilitates WM repair and long-term neurological recovery after TBI, at least in part, by inducing OPC differentiation and axonal myelination through PPAR? activation.
Three Specific Aims will be tested.
Aim 1 : Determine whether post-TBI treatment with tPAm enhances WM integrity and promotes long-term recovery.
Aim 2 : Test the hypothesis that tPAm induces OPC differentiation/maturation and promotes axonal myelination through PPAR? activation.
Aim 3 : Test the hypothesis that tPAm-induced OPC differentiation and axonal myelination are essential for the protection of WM integrity and long-term recovery after TBI. These studies are the first to investigate the potential for tPAm to foster remyelination in TBI an will identify the underlying mechanism of action, thereby setting the stage for the potential use o tPAm in the clinic.

Public Health Relevance

Recent research has discovered various neuroprotective effects by tissue plasminogen activator (tPA) that are independent of its thrombolytic activity. This proposal will test the hypothesis that intranasal delivery of tPAm (a mutant form of tPA that lacks thrombolytic activity thus without the risk of inducing intracerebral hemorrhage) improves long-term neurological outcomes after traumatic brain injury (TBI) by promoting the repair process of injured white matter. Positive results from this proposal may help identify a potential neurorestorative therapy for the prevention of long-term disability after TBI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Bellgowan, Patrick S F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Hu, Xiaoming; Leak, Rehana K; Thomson, Angus W et al. (2018) Promises and limitations of immune cell-based therapies in neurological disorders. Nat Rev Neurol 14:559-568
Jiang, Xiaoyan; Andjelkovic, Anuska V; Zhu, Ling et al. (2018) Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol 163-164:144-171
Xia, Yuguo; Pu, Hongjian; Leak, Rehana K et al. (2018) Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury. Proc Natl Acad Sci U S A 115:E9230-E9238
Cai, Wei; Yang, Tuo; Liu, Huan et al. (2018) Peroxisome proliferator-activated receptor ? (PPAR?): A master gatekeeper in CNS injury and repair. Prog Neurobiol 163-164:27-58
Yan, Jingqi; Porch, Morgan W; Court-Vazquez, Brenda et al. (2018) Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice. Proc Natl Acad Sci U S A 115:E9707-E9716
Wu, Yun; Wang, Jiayin; Shi, Yejie et al. (2017) Implantation of Brain-Derived Extracellular Matrix Enhances Neurological Recovery after Traumatic Brain Injury. Cell Transplant 26:1224-1234
Pu, Hongjian; Jiang, Xiaoyan; Wei, Zhishuo et al. (2017) Repetitive and Prolonged Omega-3 Fatty Acid Treatment After Traumatic Brain Injury Enhances Long-Term Tissue Restoration and Cognitive Recovery. Cell Transplant 26:555-569
Shi, Yejie; Jiang, Xiaoyan; Zhang, Lili et al. (2017) Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood-brain barrier disruption after ischemic brain injury. Proc Natl Acad Sci U S A 114:E1243-E1252
Wu, Yun; Wang, Jiayin; Shi, Yejie et al. (2016) Implantation of Brain-derived Extracellular Matrix Enhances Neurological Recovery after Traumatic Brain Injury. Cell Transplant :
Stetler, R Anne; Gao, Yanqin; Leak, Rehana K et al. (2016) APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury. Proc Natl Acad Sci U S A 113:E3558-67

Showing the most recent 10 out of 11 publications