Tissue-type plasminogen activator (tPA) is a serine proteinase that activates the zymogen plasminogen into plasmin. In the intravascular space tPA has a beneficial thrombolytic effect. Accordingly, recombinant tPA (rtPA) is used for the treatment of ischemic stroke patients. However, during ischemic stroke there is also an increase in tPA activity in the ischemic tissue which has been deemed as neurotoxic. In this application we postulate that tPA not only is devoid of neurotoxic effects but instead that it is a neuroprotectant that renders neurons resistant to hypoxia/ischemia. Accordingly, in this application we will test the hypothesis that in the ischemic brain tPA induces the activation of th mammalian target of rapamycin (mTOR) pathway via a mechanism independent of its thrombolytic properties, and that mTOR activation leads to hypoxia-inducible factor-1a (HIF-1a) accumulation and expression of HIF-1a-regulated genes known to have a neuroprotective effect in the ischemic brain.

Public Health Relevance

Survival of neurons to low oxygen depends upon their ability to detect and accommodate to changes in the concentration of oxygen in their environment. Neurons release tPA when exposed to low oxygen concentrations (hypoxia). In this application we will test the hypothesis that this release of tPA is the first step of a protective response tha renders neurons resistant against the deleterious effects of hypoxia/ischemia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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Emory University
Schools of Medicine
United States
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Merino, Paola; Diaz, Ariel; Jeanneret, Valerie et al. (2017) Urokinase-type Plasminogen Activator (uPA) Binding to the uPA Receptor (uPAR) Promotes Axonal Regeneration in the Central Nervous System. J Biol Chem 292:2741-2753
Merino, Paola; Diaz, Ariel; Yepes, Manuel (2017) Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) promote neurorepair in the ischemic brain. Receptors Clin Investig 4:
Diaz, Ariel; Merino, Paola; Manrique, Luis Guillermo et al. (2017) A Cross Talk between Neuronal Urokinase-type Plasminogen Activator (uPA) and Astrocytic uPA Receptor (uPAR) Promotes Astrocytic Activation and Synaptic Recovery in the Ischemic Brain. J Neurosci 37:10310-10322
Jeanneret, Valerie; Yepes, Manuel (2016) The Plasminogen Activation System Promotes Dendritic Spine Recovery and Improvement in Neurological Function After an Ischemic Stroke. Transl Stroke Res :
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