Stroke is the leading cause of morbidity and the third leading cause of mortality in the United States. Most strokes are ischemic and the majority of these are thrombotic in origin. Hemorrhagic strokes generally have worse outcomes than for ischemic strokes and hemorrhagic conversion of an ischemic stroke can markedly increase stroke severity. Thrombolytic therapy with tissue plasminogen activator (tPA) is the only approved treatment for ischemic stroke, but its use carries a significant risk for increased incidence of intracerebral hemorrhage (ICH). Thus, tPA only benefits a limited number of potential patients. The development of improved and safer therapies for stroke depends upon understanding the unique characteristics of the cerebrovasculature, and the limited benefit of tPA is due in part to its unanticipated activities in the brain beyond its well established fibrinoytic role. Several studies have demonstrated that tPA within the brain increases blood-brain-barrier (BBB) permeability after cerebral ischemia, and while there are clear benefits to some patients who receive early thrombolytic treatment, the increased risk of ICH associated with tPA demonstrate the unique challenges for its use in ischemic stroke. Ideal treatment for ischemic stroke would simultaneously promote the reestablishment of vascular patency, inhibit the development of cerebral edema, and reduce the incidence of hemorrhagic transformation. In recent studies we demonstrated that tPA within the brain activates latent platelet derived growth factor CC (PDGF- CC), which in turn increases BBB dysfunction in stroke, and that blocking this pathway significantly reduces BBB disruption, infarct size, and thrombolytic tPA induced ICH. Based on these observations, this proposal will test the hypothesis that during cerebral ischemia tPA plays a duel role, in the blood tPA promotes thrombolysis and improves reperfusion, whereas in the abluminal space tPA activates PDGF-CC which in turn promotes BBB permeability and increases the risk of ICH. We will investigate the mechanisms of this duel role of tPA, and test this hypothesis by specifically targeting tPA in blood or in the neurovascular uni (NVU), and by examining down-stream pathways regulated by PDGF-CC signaling in the NVU.
Stroke is the leading cause of disability and the third leading cause of death in the U.S. Currently the only approved treatment for stroke, thrombolysis, carries a significant risk for bleeding in the brain, which can markedly increase stroke severity. Thus, the development of improved and safer therapies for stroke will have a major impact on U.S. public health.
|Wahlgren, N; Thorén, M; Höjeberg, B et al. (2017) Randomized assessment of imatinib in patients with acute ischaemic stroke treated with intravenous thrombolysis. J Intern Med 281:273-283|
|Su, Enming Joseph; Cao, Chunzhang; Fredriksson, Linda et al. (2017) Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke. Acta Neuropathol 134:585-604|
|Fredriksson, Linda; Lawrence, Daniel A; Medcalf, Robert L (2017) tPA Modulation of the Blood-Brain Barrier: A Unifying Explanation for the Pleiotropic Effects of tPA in the CNS. Semin Thromb Hemost 43:154-168|
|Carlson, Karen-Sue B; Nguyen, Lan; Schwartz, Kat et al. (2016) Neuroserpin Differentiates Between Forms of Tissue Type Plasminogen Activator via pH Dependent Deacylation. Front Cell Neurosci 10:154|
|Lewandowski, Sebastian A; Fredriksson, Linda; Lawrence, Daniel A et al. (2016) Pharmacological targeting of the PDGF-CC signaling pathway for blood-brain barrier restoration in neurological disorders. Pharmacol Ther 167:108-119|
|Medcalf, Robert L; Lawrence, Daniel A (2016) Editorial: The Role of the Plasminogen Activating System in Neurobiology. Front Cell Neurosci 10:222|
|Szabo, R; Samson, A L; Lawrence, D A et al. (2016) Passenger mutations and aberrant gene expression in congenic tissue plasminogen activator-deficient mouse strains. J Thromb Haemost 14:1618-28|
|Pautus, Stéphane; Alami, Mouad; Adam, Fréderic et al. (2016) Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1. Sci Rep 6:36462|
|Lewandowski, Sebastian A; Nilsson, Ingrid; Fredriksson, Linda et al. (2016) Presymptomatic activation of the PDGF-CC pathway accelerates onset of ALS neurodegeneration. Acta Neuropathol 131:453-64|
|Motley, Michael P; Madsen, Daniel H; Jürgensen, Henrik J et al. (2016) A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo. Blood 127:1085-96|
Showing the most recent 10 out of 27 publications