# Urokinase-type Plasminogen Activator in the Ischemic Brain

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $434,475

## Abstract

PROJECT SUMMARY/ABSTRACT
The last two decades have witnessed a significant decrease in acute ischemic stroke mortality, that in turn has
caused a substantial increase in the number of patients that survive an ischemic stroke with different degrees of
disability. Unfortunately, despite the magnitude of this problem, to this date the mechanisms that underlie the
process of neurorepair following an ischemic injury are poorly understood, and there is no effective therapeutic
strategy to promote neurological recovery among ischemic stroke survivors. Cerebral ischemia has a harmful
impact on synaptic structure and function associated with the development of neurological deficits. Hence,
neurological recovery following an ischemic stroke requires the formation of new synaptic contacts and/or the
repair of those damaged by the ischemic injury. This is a highly dynamic process that begins with the
reestablishment and/or de novo formation of adhesive contacts between axonal boutons and postsynaptic
terminals, and is mediated by the interaction between membrane-bound adherent proteins. Neuronal cadherin
(N-Cadherin or NCAD) is an adherent protein abundantly found in the synapse, where it forms adhesive contacts
between the pre- and postsynaptic terminals. Urokinase-type plasminogen activator (uPA) is a serine proteinase
that upon binding to its receptor (uPAR) catalyzes the conversion of plasminogen into plasmin and activates cell
signaling pathways that promote cell survival, proliferation and motility. In the previous funding cycle of this
application we found that uPA is released from the presynaptic terminal of cerebral cortical neurons during the
recovery phase from an ischemic stroke, and that binding of this uPA to its receptor (uPAR) promotes the repair
of axons and dendrites damaged by the ischemic injury. In this renewal application we will test the hypothesis
that binding of either endogenous or recombinant uPA to uPAR promotes synaptic repair by inducing the
formation of NCAD-mediated adhesive contacts between the pre- and postsynaptic terminals that have been
damaged by an ischemic injury. To accomplish this goal, first we will study the mechanism whereby uPA
regulates the expression and function of NCAD in the synapse, and test the hypothesis that uPA promotes
synaptic recovery by inducing NCAD-mediated reestablishment and/or formation of new adhesive contacts
between axonal boutons and postsynaptic terminals of neurons that have suffered an ischemic injury. Then, we
will investigate the effect of uPA on the canonical Wnt-β-Catenin pathway. Finally, we will use an animal model
of cerebral ischemia to investigate if uPA-induced NCAD-mediated activation of the Wnt-β-Catenin pathway
promotes synaptic repair and neurological recovery after an ischemic injury.

## Key facts

- **NIH application ID:** 10116720
- **Project number:** 2R01NS091201-06A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Manuel Salvador Yepes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $434,475
- **Award type:** 2
- **Project period:** 2015-09-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116720

## Citation

> US National Institutes of Health, RePORTER application 10116720, Urokinase-type Plasminogen Activator in the Ischemic Brain (2R01NS091201-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10116720. Licensed CC0.

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