Physiology and regulation of drug transport across the blood brain barrier

药物跨血脑屏障转运的生理学和调节

• 批准号: 7625178
• 负责人: ROLAND J BAINTON
• 金额: $ 29.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625178
• 关键词: Accounting; Active Biological Transport; Adult; Affect; Anatomy; Animals; Apical; Astrocytes; Behavioral Assay; Biological; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; Cell Death; Cells; Characteristics; Charge; Chemicals; Clinical; Confocal Microscopy; Diffusion; Disease; Drosophila genus; Drug Controls; Drug Transport; Dyes; Ensure; Environment; Epithelium; Exclusion; G Protein-Coupled Receptor Signaling; Genes; Genetic; Genetic Screening; Goals; Hemocytes; Homologous Gene; Hypoxia; Individual; Intervention; Life; Link; Lipid Bilayers; Measures; Membrane; Methods; Modeling; Molecular Target; Neuraxis; Neuroglia; Neurons; Pathology; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Physiology; Property; Reagent; Regulation; Reporting; Research Personnel; Retina; Role; Signaling Protein; Stress; Structure; System; Testing; Therapeutic; Tight Junctions; Tissues; Vascular Endothelial Cell; Vascular Endothelium; Vertebrates; Work; Xenobiotics; base; cytotoxicity; functional outcomes; gene function; in vivo; insight; mutant; neuroprotection; novel; perineural; prevent; programs; small molecule; tool

DESCRIPTION (provided by applicant): In the central nervous system (CMS) of vertebrates, the vascular epithelium and closely apposed astrocytes are the physiologic barrier, known as the blood-brain barrier (BBB) that ensures a distinct neuronal cellular environment. At least two properties of the barrier influence the ability of substances to pass from the humoral compartment into the CNS: a diffusional barrier attributed to specialized lateralized cellular junctions in the epithelium, and the active transport of small molecules across the lipid bilayers of the cell layers. These two properties maintain the chemical separation of the compartments that protects the CMS from xenobiotics, but they also interfere with the entry of useful Pharmaceuticals into the brain. Currently, the methods for controlling therapeutic drug access to the brain are crude, inefficient, and/or dangerous in the clinical setting. Thus, safe and effective methods for controlling drug access to the CNS would have great impact on disease treatment and other clinical intervention in the CNS. We recently reported the discovery of a novel BBB regulatory system in Drosophila. This work suggests that the BBB is a dynamic structure that participates in regulating its own properties of exclusion. Our goal is to understand the regulatory mechanisms that integrate barrier properties and control access of small molecules to the CNS. Drosophila BBB anatomy has unique advantages for the simultaneous study of different BBB physiologies, specifically targeting the inter-relationship of humoral barrier epithelium and associated glia. We have shown that the properties of the Drosophila BBB are remarkably similar to those of the vertebrate BBB, and we have developed in vivo and quantitative methods for measuring the control of paracellular border function and drug transport. With these methods, we can integrate the study of physiology, anatomy, and genetics at the humoral-CNS interface and have a novel opportunity to understand the interdependence of the multiple layers of the BBB by looking simultaneously at function, pathology, and regulation. This is a powerful approach to better understand how the BBB might be manipulated for clinical purposes.

描述(申请人提供)：在脊椎动物的中枢神经系统(CMS)中，血管上皮和紧密相对的星形胶质细胞是生理屏障，称为血脑屏障(BBB)，确保独特的神经细胞环境。该屏障的至少两个性质影响物质从体液室进入中枢神经系统的能力：一种扩散屏障，归因于上皮中特殊的偏侧化细胞连接，以及小分子在细胞层的脂双层上的主动运输。这两种特性保持了保护CMS免受外来生物影响的隔室的化学隔离，但它们也干扰了有用的药物进入大脑。目前，控制治疗药物进入大脑的方法在临床环境中是原始的、低效的和/或危险的。因此，安全有效的控制药物进入中枢神经系统的方法将对中枢神经系统的疾病治疗和其他临床干预产生重大影响。我们最近报道了在果蝇中发现了一个新的血脑屏障调节系统。这项工作表明，BBB是一个动态结构，参与调节自己的排斥属性。我们的目标是了解整合屏障特性和控制小分子进入中枢神经系统的调控机制。果蝇血脑屏障的解剖学在同时研究不同的血脑屏障生理学方面具有独特的优势，特别是针对体液屏障上皮和相关胶质细胞的相互关系。我们已经证明了果蝇血脑屏障的性质与脊椎动物的血脑屏障非常相似，我们已经开发了体内和定量的方法来测量细胞旁边界功能和药物转运的控制。使用这些方法，我们可以整合体液-中枢神经系统界面的生理学、解剖学和遗传学的研究，并有一个新的机会通过同时观察功能、病理和调节来理解血脑屏障多层之间的相互依赖。这是一种强大的方法，可以更好地理解血脑屏障如何被操纵用于临床目的。