Abstract

Urokinase-type plasminogen activator (uPA) is a serine proteinase that binds to the urokinase plasminogen activator receptor (uPAR). Although it was initially believed that the main role of uPA-uPAR binding was to catalyze the conversion of plasminogen into plasmin on the cell surface, it was soon discovered that uPAR also activates cell signaling pathways in response to changes in the composition of the extracellular matrix (ECM) leading to tissue remodeling, wound healing, and cell adhesion and migration. uPA and uPAR are expressed in cerebral cortical neurons in the adult brain. In this application we will test the hypothesis that binding of uPA to uPAR in the area surrounding the necrotic core promotes dendritic spine recovery and functional improvement after an ischemic stroke.

Public Health Relevance

The interruption of the blood supply to the brain causes the death of brain cells (neurons) that results in the loss of function carried over by them. However, during the recovery phase from an ischemic stroke the neurons that survive take over the function of those lost to the stroke. In this application we will study the mechanism whereby neurons re-connect to assume new functions and how this process leads to neurological recovery after stroke.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS091201-03
Application #
9334333
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2015-09-15
Project End
2020-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322

  Publications

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; Lassègue, 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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