Dynamic control of vascular permeability in development and disease

项目总结 血管系统的完整性，特别是血脑屏障(BBB)的完整性是至关重要的。 对预防炎症和损伤引起的水肿以及对中枢神经系统的靶向治疗都很重要 病理学。按需打开BBB并在损坏时恢复其完整性的能力长期以来一直是一种 治疗学的圣杯。然而，由于对机制的了解非常有限，进展缓慢。 控制BBB完整性。事实上，目前还没有可以调节血管通透性或血脑屏障的药物。 功能。我们实验室的初步研究已经确定了两种新的、可用药的途径 有选择地调节这些过程。我们将定义这些新的渗透性调节的分子基础 途径，确定它们的生物学作用，并在此基础上开发和测试治疗应用 知识。特别是，我们建议测试一种新的基于抗体的方法来减少脑水肿 急性缺血性卒中和另一种基于抗体的按需增加血脑屏障的方法 足以将药物输送到大脑的渗透性。

PROJECT SUMMARY The integrity of the vasculature in general and the blood-brain barrier (BBB) in particular, is of critical importance both for prevention of edema due to inflammation and injury and for targeted treatment of CNS pathologies. The ability to open BBB “on demand” and to restore its integrity when damaged, has long been a holy grail for therapeutics. Yet the progress has been slow due to very limited understanding of mechanisms controlling BBB integrity. Indeed, no drugs currently exist that can regulate vascular permeability or BBB function. Preliminary studies from our laboratories have identified two novel, druggable pathways that selectively regulate these processes. We will define molecular basis of these novel permeability-regulating pathways, determine their biological role and develop and test therapeutic applications based on this knowledge. In particular, we propose to test a new antibody-based approach to the reduction of brain edema in acute ischemic stroke and another antibody based approach to on demand increase in the blood-brain barrier permeability sufficient to allow delivery of drugs to the brain.