tPA is a Neuroprotectant in the Ischemic Brain

说明(申请人提供)：组织型纤溶酶原激活剂(TPA)是一种丝氨酸蛋白酶，能将酶原纤溶酶原激活为纤溶酶。在血管内，tPA具有良好的溶栓作用。因此，重组组织型纤溶酶原激活剂(RtPA)被用于治疗缺血性中风患者。然而，在缺血性中风期间，缺血组织中的tPA活性也会增加，这被认为是神经毒性的。在这个应用中，我们假设tPA不仅没有神经毒性作用，而且它是一种神经保护剂，使神经元对缺氧/缺血产生抵抗。因此，在本应用中，我们将检验这样一种假设，即在缺血脑中，tPA通过一种独立于其溶栓特性的机制诱导哺乳动物雷帕霉素靶标(MTOR)途径的激活，以及mTOR激活导致缺氧诱导因子-1a(HIF-1a)积累和已知的具有神经保护作用的HIF-1a调节基因的表达。

DESCRIPTION (provided by applicant): 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.