Regulation of Blood Brain Barrier Permeability

描述（由申请人提供）：治疗脑疾病的一个关键挑战是克服将诊断或治疗剂递送到脑的特定区域的困难。这些障碍中最主要的是神经保护性血脑屏障（BBB），这是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，可能会导致药物或基因靶向受伤或患病大脑的创新新策略。斑马鱼是一种小型的、遗传上易于控制的硬骨鱼，具有与哺乳动物相似的基本特征。在本申请中，我们将测试的假设，即斑马鱼构成一种新的在健康和疾病条件下的BBB发育和生理研究的体内模型。在第一个目标中，为了揭示指示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，在生理条件下和化学模拟缺氧条件下，在发育过程中和成人中描绘微血管内皮细胞基因表达。最有希望的候选基因和途径的功能将通过敲除方法进行分析。在第二个目标中，使用本文所述的血管通透性报告基因转基因系，我们将进行第一次高通量化学筛选，其集中于调节神经血管单元中屏障通透性的信号转导途径.这些研究有可能更好地了解BBB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，并为如何在治疗上操纵血管通透性提供新的思路。总之，他们的目标是提供新的信息，由最近成立的国际脑屏障协会（IBBS）优先为BBB研究领域的进步和改善大脑疾病的治疗。 公共卫生相关性：血脑屏障（BBB）的重要性通过与有缺陷的BBB相关的中枢神经系统（CNS）的大量病理来说明。中风、水肿、脑创伤和多发性硬化症的许多症状是由于伴随原发性损伤的BBB的破裂。此外，BBB在许多神经系统疾病的治疗中提供了顽固的障碍，因为它极大地阻碍了药物向CNS的递送。在这个提议中，我们利用斑马鱼血脑屏障与哺乳动物血脑屏障的相似性，为脑屏障科学的转化研究提供了一个前所未有的框架。

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.