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.
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.
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