Regulation of Blood Brain Barrier Permeability

描述（由申请人提供）：脑疾病治疗的一个关键挑战是克服将诊断或治疗药物输送到大脑特定区域的困难。这些障碍中最主要的是保护神经的血脑屏障（BBB），这是对大多数大分子和小化合物的物理和代谢屏障。提高我们对调节大脑微血管通透性的基本分子和细胞机制的理解，可能会导致针对受伤或患病大脑的药物或基因靶向的创新策略。斑马鱼是一种小型的、遗传上易于控制的硬骨鱼，它的血脑屏障与哺乳动物的血脑屏障具有相同的基本特征。在这个应用中，我们将测试斑马鱼在健康和疾病条件下构成血脑屏障发育和生理研究的新型体内模型的假设。在第一个目标中，为了揭示指导血脑屏障形成和维持的信号，我们将利用新的体内血脑屏障标记技术来分析微血管内皮细胞在发育和成人、生理条件和化学模拟缺氧条件下的基因表达。最有希望的候选基因和途径的功能将通过敲低方法进行分析。在第二个目标中，使用本文描述的血管通透性报告转基因系，我们将以调节神经血管单元屏障通透性的信号转导途径为中心，进行第一次高通量化学筛选。这些研究有可能更好地了解血脑屏障内皮细胞的分子组成，并为更合理的药物递送策略铺平道路，同时为如何在治疗上操纵血管通透性提供新的线索。总之，他们的目标是为最近成立的国际脑屏障协会（IBBS）提供新的信息，以促进脑屏障研究领域的发展和改善脑部疾病的治疗。

DESCRIPTION (provided by applicant): A key challenge for the treatment of brain diseases is overcoming the difficulty of delivering diagnostic or therapeutic agents to specific regions of the brain. Chief amongst these obstacles is the neuroprotective Blood-Brain Barrier (BBB), both a physical and metabolic barrier to most macromolecules and small compounds. Improving our understanding of the basic molecular and cellular mechanisms that regulate brain microvasculature permeability could lead to innovative new strategies for drug or gene targeting to the injured or diseased brain. The zebrafish, a small, genetically tractable, teleost fish, possesses a BBB that shares the cardinal features of its mammalian counterpart. In this application, we will test the hypothesis that the zebrafish constitutes a novel in vivo model for BBB developmental and physiological studies in both health and disease conditions. In the first aim, in order to uncover the signals that instruct BBB formation and maintenance, we will take advantage of novel in vivo BBB labeling techniques to profile microvascular endothelial cell gene expression during both development and in adults, under physiological conditions and under chemically-mimicked hypoxia. The function of the most promising candidate genes and pathways will be analyzed via knock down approaches. In the second aim, using a herein described vascular permeability reporter transgenic line, we will perform the first high- throughput chemical screen centered on signal transduction pathways that modulate barrier permeability in the neurovascular unit. These studies have the potential to provide a better understanding of the molecular composition of the BBB endothelial cells and should pave the way towards more rationale drug delivery strategies as well as shed new lights onto how vascular permeability could be manipulated therapeutically. Taken together, they aim to provide new information as prioritized by the recently formed International Brain Barriers Society (IBBS) for the advancement of the field of BBB research and the improvement of brain disorder treatments. PUBLIC HEALTH RELEVANCE: The importance of the Blood-Brain Barrier (BBB) is illustrated by the large number of pathologies of the central nervous system (CNS) that are associated with a defective BBB. Many of the symptoms of stroke, edema, brain traumas and multiple sclerosis are due to a breakdown of the BBB that accompanies the primary insult. Furthermore, the BBB provides a stubborn obstacle in the treatment of many neurological diseases as it greatly impedes the delivery of drugs to the CNS. In this proposal we take advantage of the similarity of the zebrafish BBB to its mammalian counterpart to provide an unprecedented framework for translational research in brain barrier science.