White matter (WM) injury, characterized by demyelination and loss of axonal integrity, is an important cause of long-term sensorimotor and cognitive deficits after stroke. WM repair, including axonal regrowth, oligodendrogenesis and the myelination of demyelinated or newly generated axons, would help rebuild neuronal connectivity and reestablish axonal signal conduction. Unfortunately, the adult brain has limited capacity for remyelination, at least in part due to the failure of differentiation of oligodendrocyte precursor cells (OPCs) into mature, myelinating oligodendrocytes (OLs). Thus, interventions that promote OPC differentiation may facilitate axonal remyelination, WM repair and long-term neurological recovery in stroke patients. Human recombinant tissue plasminogen activator (tPA) is the only FDA approved drug for the thrombolytic treatment of ischemic stroke. However, recent research has discovered various neuroprotective effects by tPA that are independent of its thrombolytic activity. Moreover, intranasal administration of tPA improves functional recovery and promotes axonal sprouting after stroke. Currently, the use of tPA is limited to the first 4.5 hr after the oset of stroke, as beyond this time window it tremendously increases the risk of intracerebral hemorrhage (ICH) via BBB damage. This proposal will investigate the efficacy of tPAm, a mutant form of tPA that lacks thrombolytic activity (thus would not induce ICH), in rodent models of ischemic stroke. We have found in primary cultures that tPAm potently promotes the differentiation of OPCs into mature OLs. This effect of tPAm depends on its activation of PPAR, a master transcriptional factor that regulates cell differentiation and possesses antioxidant and anti-inflammatory functions. In vivo studies suggest that lack of endogenous tPA exacerbates functional deficits and WM injury up to 35 days after distal MCAO. In contrast, tPAm administration 6 hr after transient MCAO improved long-term neurological behavior and WM integrity. Our results suggest that tPAm enhances post-stroke WM integrity, at least in part, by promoting OPC differentiation and axonal myelination. This proposal will investigate the novel WM repair-enhancing role of tPAm and the underlying mechanisms. We will test the following overarching hypothesis: Treatment with protease-inactive tPAm facilitates WM repair and long-term neurological recovery after stroke, at least in part by promoting OPC differentiation and axonal myelination through PPAR. Both young adult and aged mice will be tested.
Three Specific Aims are proposed.
Aim 1 : Determine whether post-stroke treatment with the protease-inactive tPAm enhances WM integrity and promotes long-term neurological recovery.
Aim 2 : Test the hypothesis that tPAm induces OPC differentiation/maturation and promotes axonal myelination via PPAR? activation. Primary OPCs and a neuron-OPC co-culture system will be applied to test this hypothesis.
Aim 3 : Test the hypothesis that tPAm-induced OPC differentiation and axonal myelination/remyelination are essential for its beneficial effects on WM integrity and long-term neurological recovery after stroke.
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 stroke 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 stroke.
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