Traumatic brain injury (TBI) remains a major cause of death and long-term morbidity. Cerebral edema is a common and ominous sequel of severe TBI which results from loss of blood-brain-barrier (BBB) integrity and hemorrhage in the affected zone. This application is predicated on recent data showing that tPA-/- mice are relatively protected from developing cerebral edema and cortical necrosis after TBI and our finding that tPA increases BBB permeability both directly and indirectly by inducing vasorelaxation through extra-fibrinolytic mechanisms that involve signal transduction through the low density lipoprotein related receptor (LRP) and the integrin avb3. Here, we propose to study how the extra-fibrinolytic activities of tPA modulate BBB permeability, vasorelexation, cerebral edema and neurological outcome in experimental TBI. Our approach includes basic research into the mechanism of tPA-mediated signal transduction using antagonists and tPA variants that dissociate its vasoactive and catalytic properties through three inter-related specific aims.
In Specific Aim 1 we will study the molecular determinants required to form complexes between avb3 and LRP and mechanism by which tPA disrupts these complexes and induces BBB permeability and vasorelaxation.
In Specific Aim 2 the effect of intravascular thrombosis on the development of post-traumatic brain injury will be elucidated using approaches to isolate the fibrinolytic and signal transduction activities of tPA.
In Specific Aim 3 the effect of antagonists to LRP and avb3 and tPA variants selectively lacking fibrinolytic or extra-fibrinolytic function in the sequelae of TBI will be examined in wild type and tPA-/- mice. Also, a new approach to deliver tPA to traumatized vessels will be evaluated using platelet-tPA expressing transgenic mice. Together, these studies will provide new understanding of the role of tPA in mediating CNS injury and novel cellular targets and new formulations of tPA that may improve clinical outcome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077760-04
Application #
7603049
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Kindzelski, Andrei L
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2009
Total Cost
$384,759
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Abu-Fanne, Rami; Maraga, Emad; Abd-Elrahman, Ihab et al. (2016) ?-Defensins Induce a Post-translational Modification of Low Density Lipoprotein (LDL) That Promotes Atherosclerosis at Normal Levels of Plasma Cholesterol. J Biol Chem 291:2777-86
Armstead, William M; Bohman, Leif-Erik; Riley, John et al. (2013) tPA-S(481)A prevents impairment of cerebrovascular autoregulation by endogenous tPA after traumatic brain injury by upregulating p38 MAPK and inhibiting ET-1. J Neurotrauma 30:1898-907
Armstead, William M; Riley, John; Cines, Douglas B et al. (2012) Combination therapy with glucagon and a novel plasminogen activator inhibitor-1-derived peptide enhances protection against impaired cerebrovasodilation during hypotension after traumatic brain injury through inhibition of ERK and JNK MAPK. Neurol Res 34:530-7
Armstead, William M; Ganguly, Kumkum; Riley, John et al. (2012) RBC-coupled tPA Prevents Whereas tPA Aggravates JNK MAPK-Mediated Impairment of ATP- and Ca-Sensitive K Channel-Mediated Cerebrovasodilation After Cerebral Photothrombosis. Transl Stroke Res 3:114-21
Armstead, William M; Riley, John; Yarovoi, Serge et al. (2012) tPA-S481A prevents neurotoxicity of endogenous tPA in traumatic brain injury. J Neurotrauma 29:1794-802
Armstead, William M; Riley, John; Cines, Douglas B et al. (2011) tPA contributes to impairment of ATP and Ca sensitive K channel mediated cerebrovasodilation after hypoxia/ischemia through upregulation of ERK MAPK. Brain Res 1376:88-93
Fanne, Rami Abu; Nassar, Taher; Mazuz, Achinoam et al. (2011) Neuroprotection by glucagon: role of gluconeogenesis. J Neurosurg 114:85-91
Armstead, William M; Kiessling, J Willis; Riley, John et al. (2011) tPA contributes to impaired NMDA cerebrovasodilation after traumatic brain injury through activation of JNK MAPK. Neurol Res 33:726-33
Armstead, William M; Kiessling, J Willis; Cines, Douglas B et al. (2011) Glucagon protects against impaired NMDA-mediated cerebrovasodilation and cerebral autoregulation during hypotension after brain injury by activating cAMP protein kinase A and inhibiting upregulation of tPA. J Neurotrauma 28:451-7
Makarova, Anastasia M; Lebedeva, Tatiana V; Nassar, Taher et al. (2011) Urokinase-type plasminogen activator (uPA) induces pulmonary microvascular endothelial permeability through low density lipoprotein receptor-related protein (LRP)-dependent activation of endothelial nitric-oxide synthase. J Biol Chem 286:23044-53

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