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: 7841693
• 负责人: ROLAND J BAINTON
• 金额: $ 29.06万
• 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/7841693
• 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（由申请人提供）：在脊椎动物的中枢神经系统（CMS）中，血管上皮和紧密贴壁的星形胶质细胞是生理屏障，称为血脑屏障（BBB），可确保独特的神经元细胞环境。屏障的至少两个特性影响物质从体液隔室进入CNS的能力：归因于上皮中专门的偏侧细胞连接的扩散屏障，以及小分子穿过细胞层的脂质双层的主动运输。这两种性质维持了保护CMS免受外源性物质影响的隔室的化学分离，但它们也干扰了有用药物进入大脑。目前，用于控制治疗药物进入大脑的方法在临床环境中是粗糙、低效和/或危险的。因此，用于控制药物进入CNS的安全有效的方法将对CNS中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一种新的血脑屏障调节系统。这项工作表明，血脑屏障是一个动态的结构，参与调节其自身的排斥特性。我们的目标是了解整合屏障特性和控制小分子进入CNS的调节机制。果蝇血脑屏障解剖学具有独特的优势，同时研究不同的血脑屏障生理，特别是针对体液屏障上皮细胞和相关的胶质细胞的相互关系。我们已经表明，果蝇血脑屏障的属性是非常相似的脊椎动物血脑屏障，我们已经开发出在体内和定量的方法来测量控制细胞旁的边界功能和药物转运。有了这些方法，我们可以整合生理学，解剖学和遗传学在体液-中枢神经系统界面的研究，并有一个新的机会，通过同时查看功能，病理学和调节来了解BBB多层的相互依赖性。这是一种强大的方法，可以更好地了解如何操纵BBB用于临床目的。