Traumatic brain injury (TBI) remains a major medical problem, resulting in 50,000 deaths/year in the US and is an important cause of long-term morbidity. In the present application we propose to explore the mechanism of action of a tPA mutant (tPA-S481A) that lacks fibrinolytic activity and does not prevent loss of blood-brain-barrier (BBB) permeability exerts a powerful neuroprotective effect. Our data help explain this seemingly paradoxical outcome by showing the beneficial effects of maintaining BBB permeability by 1) accelerating the clearance of neurotoxic amino acids and 2) promoting the delivery of tPA-S481A to brain parenchyma where it competes with endogenous tPA for activation of the NMDA receptor and thereby prevents neuronal apoptosis. These studies provide both fundamental new insights into the function of BBB permeability post-TBI and identify a novel mechanism of neuroprotection.

Public Health Relevance

We will explore the mechanism of action of a tPA mutant that exerts a powerful neuroprotective effect against traumatic brain injury (TBI) in the absence of fibrinolytic activity and without preventing loss blood-brain-barrier integrity. We will explore this seemingly paradoxical outcome by showing how opening of the BBB during brain injury provides neuroprotection by clearing neurotoxic agents and ameliorating apoptosis by preventing NMDA receptor activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS064447-02
Application #
8054407
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Hicks, Ramona R
Project Start
2010-04-01
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$196,000
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Larusch, Gretchen A; Merkulova, Alona; Mahdi, Fakhri et al. (2013) Domain 2 of uPAR regulates single-chain urokinase-mediated angiogenesis through ?1-integrin and VEGFR2. Am J Physiol Heart Circ Physiol 305:H305-20