Novel approaches for neuroprotection

描述(申请人提供)：创伤性脑损伤(TBI)仍然是一个主要的医学问题，在美国每年导致50,000人死亡，也是长期发病率的重要原因。在目前的应用中，我们建议探索tPA突变体(tPA-S481a)的作用机制，该突变体缺乏纤溶活性，不能防止血脑屏障(BBB)通透性的丧失，具有强大的神经保护作用。我们的数据通过显示维持血脑屏障通透性的有益效果来帮助解释这一看似矛盾的结果：1)加速神经毒性氨基酸的清除；2)促进tPA-S481a输送到脑实质，在那里它与内源性tPA竞争激活NMDA受体，从而防止神经元凋亡。这些研究为脑创伤后血脑屏障通透性的功能提供了基本的新见解，并确定了一种新的神经保护机制。 公共卫生相关性：我们将探索一种tPA突变体的作用机制，该突变体在缺乏纤溶活性和不防止血脑屏障完整性丧失的情况下，对创伤性脑损伤(TBI)发挥强大的神经保护作用。我们将通过展示脑损伤期间开放血脑屏障如何通过清除神经毒剂来提供神经保护，并通过阻止NMDA受体激活来改善细胞凋亡，从而探索这一看似自相矛盾的结果。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) remains a major medical problem, resulting in 50,000 deaths/year in the US and is an important cause of long-term morbidity. In the present application we propose to explore the mechanism of action of a tPA mutant (tPA-S481A) that lacks fibrinolytic activity and does not prevent loss of blood-brain-barrier (BBB) permeability exerts a powerful neuroprotective effect. Our data help explain this seemingly paradoxical outcome by showing the beneficial effects of maintaining BBB permeability by 1) accelerating the clearance of neurotoxic amino acids and 2) promoting the delivery of tPA-S481A to brain parenchyma where it competes with endogenous tPA for activation of the NMDA receptor and thereby prevents neuronal apoptosis. These studies provide both fundamental new insights into the function of BBB permeability post-TBI and identify a novel mechanism of neuroprotection. PUBLIC HEALTH RELEVANCE: We will explore the mechanism of action of a tPA mutant that exerts a powerful neuroprotective effect against traumatic brain injury (TBI) in the absence of fibrinolytic activity and without preventing loss blood-brain-barrier integrity. We will explore this seemingly paradoxical outcome by showing how opening of the BBB during brain injury provides neuroprotection by clearing neurotoxic agents and ameliorating apoptosis by preventing NMDA receptor activation.