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Dynamic control of vascular permeability in development and disease

发育和疾病过程中血管通透性的动态控制

基本信息

批准号：
9977245
负责人：
Anne Christine Eichmann
金额：
$ 82.93万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977245
关键词：
Acute Adherens Junction Adult Antibodies Area Binding Biological Biological Testing Blood - brain barrier anatomy Blood Vessels Brain Brain Edema Brain Injuries Cell membrane Complex Data Development Disease Drug Delivery Systems Edema Endothelium Event Extravasation Human Inflammation Injury Integral Membrane Protein Ischemic Stroke KDR gene Knock-out Knockout Mice Knowledge Laboratories Molecular Mus Neurology PTPRJ gene Pathology Pathway interactions Permeability Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Prevention Process Protein Dephosphorylation Protein Tyrosine Phosphatase Regulation Role SRC gene Site Stroke Testing Therapeutic Time Tyrosine Vascular Endothelial Growth Factors Vascular Permeabilities aged base blood-brain barrier function blood-brain barrier permeabilization cadherin 5 experimental study fibroglycan macromolecule mutant novel novel strategies novel therapeutic intervention novel therapeutics response stroke model stroke therapy targeted treatment therapeutic evaluation

项目摘要

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.

项目摘要血管系统的完整性，特别是血脑屏障（BBB），是至关重要的对于预防炎症和损伤引起的水肿以及中枢神经系统的靶向治疗都很重要病理学“按需”打开血脑屏障并在受损时恢复其完整性的能力长期以来一直是一个难题。治疗学的圣杯然而，由于对机制的了解非常有限，进展缓慢控制血脑屏障的完整性事实上，目前还没有药物可以调节血管通透性或BBB 功能我们实验室的初步研究已经确定了两种新的，可药物化的途径，选择性地调节这些过程。我们将定义这些新的渗透性调节的分子基础，途径，确定其生物学作用，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，急性缺血性中风和另一种基于抗体的方法来增加血脑屏障渗透性足以允许药物递送到大脑。