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tPA is a Neuroprotectant in the Ischemic Brain

tPA 是缺血性脑部的神经保护剂

基本信息

批准号：
9208814
负责人：
Manuel Salvador Yepes
金额：
$ 35.22万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9208814
关键词：
Activator Appliances Acute Address Alteplase Blood - brain barrier anatomy Brain Brain Hypoxia-Ischemia Cell physiology Cerebral Ischemia Cerebrum Clinical Detection Environment Enzyme Precursors Excitatory Neurotoxins FRAP1 gene Foundations Genes Genetic Hemorrhage Hour Hypoxia Hypoxia Inducible Factor Ischemic Stroke Mediating Metabolic N-Methylaspartate Nervous System Physiology Neuraxis Neurological outcome Neurons Neuroprotective Agents Oxygen Pathway interactions Patients Permeability Plasmin Plasminogen Plasminogen Activator Play Property Publishing Receptor Activation Recombinants Recovery Resistance Resources Risk Role Serine Protease Signal Pathway Signal Transduction Study Section Synapses Testing Therapeutic Therapeutic Effect Tissues Work base clinically relevant hypoxia inducible factor 1 improved nanocarrier neuron loss neuronal survival neuroprotection neurotoxic novel novel strategies overexpression public health relevance receptor response targeted delivery thrombolysis transcription factor

项目摘要

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.

描述（由申请人提供）：组织型纤溶酶原激活剂（tPA）是一种丝氨酸蛋白酶，可将酶原纤溶酶原激活为纤溶酶。在血管内，tPA具有有益的溶栓作用。因此，重组tPA （rtPA）被用于缺血性脑卒中患者的治疗。然而，在缺血性中风期间，缺血组织中的tPA活性也有所增加，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，相反，它是一种神经保护剂，使神经元抵抗缺氧/缺血。因此，在本应用中，我们将验证以下假设：在缺血性脑中，tPA通过独立于其溶栓特性的机制诱导哺乳动物雷帕霉素靶蛋白（mTOR）途径的激活，mTOR激活导致缺氧诱导因子-1a （HIF-1a）的积累和HIF-1a调节基因的表达，这些基因已知在缺血性脑中具有神经保护作用。