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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS079331-01A1
Application #
8495006
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$341,250
Indirect Cost
$122,500
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Diaz, Ariel; Merino, Paola; Manrique, Luis G et al. (2018) Urokinase-type plasminogen activator (uPA) protects the tripartite synapse in the ischemic brain via ezrin-mediated formation of peripheral astrocytic processes. J Cereb Blood Flow Metab :271678X18783653
Diaz, Ariel; Yepes, Manuel (2018) Urokinase-type plasminogen activator promotes synaptic repair in the ischemic brain. Neural Regen Res 13:232-233
Yepes, Manuel (2018) Urokinase-type Plasminogen Activator Promotes Synaptic Recovery in the Ischemic Brain. J Transl Neurosci 3:
Merino, Paola; Diaz, Ariel; Manrique, Luis Guillermo et al. (2018) Urokinase-type plasminogen activator (uPA) promotes ezrin-mediated reorganization of the synaptic cytoskeleton in the ischemic brain. J Biol Chem 293:9234-9247
Hernandes, Marina S; Lass├Ęgue, Bernard; Hilenski, Lula L et al. (2018) Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain. J Neuroinflammation 15:45
Merino, Paola; Yepes, Manuel (2018) Urokinase-type Plasminogen Activator Induces Neurorepair in the Ischemic Brain. J Neurol Exp Neurosci 4:24-29
Jeanneret, Valerie; Ospina, Juan P; Diaz, Ariel et al. (2018) Tissue-type plasminogen activator protects the postsynaptic density in the ischemic brain. J Cereb Blood Flow Metab 38:1896-1910
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

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