Drug Transport Mechanisms at the Blood-CSF Barrier and Effect of Aging

血脑脊液屏障的药物转运机制和衰老的影响

• 批准号: 10371411
• 负责人: Joanne Wang
• 金额: $ 21.72万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371411
• 关键词: ABCB1 gene; Active Biological Transport; Aging; Alzheimer' s Disease; Anions; Apical; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood capillaries; Brain; Brain Diseases; Cations; Central Nervous System Diseases; Characteristics; Choroid Plexus Epithelium; Data; Development; Drug Delivery Systems; Drug Efflux; Drug Kinetics; Drug Targeting; Drug Transport; Epithelial Cells; Excision; Extracellular Fluid; Fluorescein; Future; Goals; Health; Infection; Investigation; Kidney; Knockout Mice; Laboratories; Left; Liver; Malignant neoplasm of brain; Mediating; Metabolic; Methotrexate; Molecular; Morphology; Multidrug Resistance-Associated Proteins; Multiple Sclerosis; Mus; Neurohormones; Neurons; OATP Transporters; Organ; Parkinson Disease; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Play; Process; Property; Proteomics; Public Health; Quantitative Reverse Transcriptase PCR; Research; Role; Side; Stroke; Structure; Structure of choroid plexus; System; Testing; Therapeutic Effect; Tissue imaging; Tissues; Toxin; Transmembrane Transport; Transport Process; Work; Xenobiotics; age effect; age related; apical membrane; basolateral membrane; blood cerebrospinal fluid barrier; brain parenchyma; design; drug candidate; drug clearance; drug development; drug discovery; drug disposition; imaging approach; mouse model; nervous system disorder; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; protein expression; solute; uptake; wasting

Research Summary Brain disorders, especially age-related neurological diseases, constitute a major public health problem in the developed world. Despite the urging needs for new and more effective drugs to treat brain diseases, development of CNS drugs remains challenging. To exert their therapeutic effects, CNS-targeted drugs must cross the brain-blood barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) and maintain minimal effective concentrations in the brain. The BBB and BCSFB are not only physical barriers but also express a spectrum of multispecific drug transporters to actively remove drugs and other xenobiotics from the brain. The choroid plexus epithelial (CPE) cells forming the BCSFB play an essential role in brain removal of drugs and metabolites through secretion of the CSF and active transport of solutes from the CSF into the blood circulation. Nevertheless, little is known regarding the molecular and cellular mechanisms governing drug transport show marked morphological and functional changes developed a live tissue imaging approach in isolated murine choroid plexus to analyze organic anion and cation transport processes in CPE cells. Our processes at the BCSFB. Furthermore, the CPE cells are known to changes during aging but it is unknown if these age-dependent impact the expression and activity of transporters at the BCSFB. Our laboratory recently preliminary studies suggest that large amphipathic organic anions (OAs) are rapidly cleared from the CSF side into the blood capillary side by a highly functional BCSFB transport system likely consisting of organic anion transporting polypeptides (Oatps) at the apical membrane and multidrug resistance-associated proteins (Mrps) at the basolateral membrane. We hypothesize that Oatps mediate the first and rate-limiting step in the transport of structurally diverse amphipathic OAs across the BCSFB and that the expression and activity of Oatps and Mrps at the BCSFB are regulated by aging. The goals of this application are to determine the functional characteristics of the BCSFB amphipathic OA transport system, define the role of Oatp1a transporters in BCSFB transport, and explore age-dependent changes in transporter expression and function at the BCSFB. The proposed studies will build a functional and mechanistic framework for a major xenobiotic clearance pathway at the BCSFB and pave the way for future studies to investigate the impact of BCSFB transporters and aging on CNS drug disposition, pharmacokinetics and pharmacodynamics.

研究总结 脑部疾病，特别是与年龄有关的神经疾病，构成了中国的一个主要公共卫生问题 发达国家。尽管迫切需要新的、更有效的药物来治疗脑部疾病， 中枢神经系统药物的开发仍然具有挑战性。为了发挥其治疗效果，针对中枢神经系统的药物必须 跨越脑-血屏障(BBB)和血-脑脊液屏障(BCSFB)，维持最低限度 大脑中的有效浓度。BBB和BCSFB不仅是物理上的障碍，而且还表达了 多特定药物转运体的光谱，以积极地从大脑中清除药物和其他外源物质。这个 形成BCSFB的脉络丛上皮(CPE)细胞在脑内药物和药物的清除中起着至关重要的作用 通过脑脊液的分泌和脑脊液中溶质的主动运输进入血液循环的代谢产物。 然而，人们对控制药物转运的分子和细胞机制知之甚少。 显示标记的形态和功能 变化 建立了一种分离小鼠的活体组织成像方法 脉络丛以分析有机阴阳离子在CPE细胞中的转运过程。我们的 BCSFB的流程。此外，已知CPE细胞 老化过程中的变化，但 目前尚不清楚这些年龄相关因素是否会影响脑组织中 BCSFB的运输员。我们的实验室最近 初步研究 提示大的两亲性有机阴离子(OA)从脑脊液侧迅速清除到血液中 毛细管旁可能由有机阴离子传输组成的高功能BCSFB传输系统 顶膜多肽(OATPs)和根尖膜多药耐药相关蛋白(MRPs) 基底侧膜。我们假设，OATP在运输的第一步和限速步骤中起中介作用。 跨BCSFB的结构多样化的两亲性OAS以及OATP和MRP的表达和活性 在BCSFB是受衰老调节的。本应用程序的目标是确定功能特征 定义Oatp1a转运体在BCSFB转运体中的作用，以及 探索BCSFB转运蛋白表达和功能的年龄相关性变化。建议进行的研究 将为BCSFB的主要外源生物清除途径建立一个功能和机制框架，并 为未来研究BCSFB转运蛋白和衰老对中枢药物的影响铺平道路 处理、药代动力学和药效学。