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
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 :
Yepes, M; Wu, F; Torre, E et al. (2016) Tissue-type plasminogen activator induces synaptic vesicle endocytosis in cerebral cortical neurons. Neuroscience 319:69-78
Wu, Fang; Torre, Enrique; Cuellar-Giraldo, David et al. (2015) Tissue-type plasminogen activator triggers the synaptic vesicle cycle in cerebral cortical neurons. J Cereb Blood Flow Metab 35:1966-76
An, J; Haile, W B; Wu, F et al. (2014) Tissue-type plasminogen activator mediates neuroglial coupling in the central nervous system. Neuroscience 257:41-8
Wu, Fang; Catano, Marcela; Echeverry, Ramiro et al. (2014) Urokinase-type plasminogen activator promotes dendritic spine recovery and improves neurological outcome following ischemic stroke. J Neurosci 34:14219-32
Wu, Fang; Echeverry, Ramiro; Wu, Jialing et al. (2013) Tissue-type plasminogen activator protects neurons from excitotoxin-induced cell death via activation of the ERK1/2-CREB-ATF3 signaling pathway. Mol Cell Neurosci 52:9-19
Wu, Fang; Nicholson, Andrew D; Haile, Woldeab B et al. (2013) Tissue-type plasminogen activator mediates neuronal detection and adaptation to metabolic stress. J Cereb Blood Flow Metab 33:1761-9

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