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 #
5R01NS079331-02
Application #
8608614
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
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$307,125
Indirect Cost
$110,250
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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; 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