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：
10421063
负责人：
Anne Christine Eichmann
金额：
$ 81.38万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10421063
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.

项目摘要脉管系统的完整性一般，尤其是血脑屏障（BBB）的完整性至关重要重要性对于预防因感染和损伤以及CNS的靶向治疗而重要的重要性病理。长期以来，可以在损坏时打开BBB“按需”并恢复其完整性的能力长期以来一直是圣杯治疗。然而，由于对机制的理解非常有限，进展一直很慢控制BBB完整性。实际上，目前尚无可以调节血管通透性或BBB的药物功能。我们实验室的初步研究已经确定了两种新颖的可吸毒途径有选择地调节这些过程。我们将定义这些新型渗透性调节的分子基础途径，基于此确定其生物学作用，开发和测试治疗应用知识。特别是，我们建议测试一种基于抗体的新方法，以减少大脑水肿急性缺血性卒中和另一种基于抗体的方法，以增加血脑屏障的需求增加渗透性足以使药物向大脑输送。