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，特别是与年龄相关的神经系统疾病，构成了当今世界的主要公共卫生问题 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充满挑战。中枢神经系统靶向药物要发挥治疗作用，必须 穿过脑血屏障（BBB）和血脑脊液屏障（BCSFB）并保持最低限度 大脑中的有效浓度。 BBB和BCSFB不仅是物理屏障，而且表达了一种 一系列多特异性药物转运蛋白，可主动从大脑中清除药物和其他异生物质。这 形成 BCSFB 的脉络丛上皮 (CPE) 细胞在大脑清除药物和 通过脑脊液的分泌和将溶质从脑脊液主动转运到血液循环中来产生代谢物。 然而，人们对控制药物转运的分子和细胞机制知之甚少。 显示出明显的形态和功能 变化 开发了一种离体小鼠活体组织成像方法 脉络丛来分析 CPE 细胞中的有机阴离子和阳离子转运过程。我们的 BCSFB 的流程。此外，已知 CPE 细胞 衰老过程中会发生变化，但是 目前尚不清楚这些年龄依赖性是否会影响 BCSFB 的运输机。我们实验室最近 初步研究 表明大的两亲性有机阴离子（OA）迅速从脑脊液侧清除到血液中 毛细管侧由功能强大的 BCSFB 传输系统组成，可能由有机阴离子传输组成 顶膜多肽（Oatps）和多药耐药相关蛋白（Mrps） 基底外侧膜。我们假设 Oatps 介导了转运过程中的第一步和限速步骤。 BCSFB 中结构多样的两亲性 OA，以及 Oatps 和 Mrps 的表达和活性 BCSFB 受老化调节。该应用程序的目标是确定功能特性 BCSFB 两亲性 OA 转运系统，定义 Oatp1a 转运蛋白在 BCSFB 转运中的作用，以及 探索 BCSFB 转运蛋白表达和功能的年龄依赖性变化。拟议的研究 将为 BCSFB 的主要外源物清除途径建立功能和机制框架 为未来研究 BCSFB 转运蛋白和衰老对 CNS 药物的影响铺平道路 处置、药代动力学和药效学。