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.

研究摘要 脑部疾病，尤其是与年龄有关的神经疾病，构成了公共卫生问题 发达世界。尽管需要新的，更有效的药物来治疗脑部疾病，但仍需要 CNS药物的开发仍然具有挑战性。为了发挥其治疗作用，必须以CNS为目标的药物 越过脑血屏障（BBB）和脑脊液屏障（BCSFB）并保持最小 大脑中有效浓度。 BBB和BCSFB不仅是物理障碍，而且表达 多特异性药物转运蛋白的光谱从大脑中积极去除药物和其他异种生物。这 形成BCSFB的脉络丛上皮（CPE）细胞在去除药物和 代谢物通过CSF的分泌以及从CSF进入血液循环的溶质的主动运输。 然而，关于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 更改 在孤立的小鼠中开发了一种活组织成像方法 脉络丛分析CPE细胞中有机阴离子和阳离子转运过程。我们的 BCSFB的过程。此外，已知CPE细胞已知 衰老期间的变化 这些年龄依赖性是否影响 BCSFB的转运蛋白。我们最近的实验室 初步研究 表明大型有机阴离子（OA）从CSF迅速清除到血液中 毛细管侧由高功能的BCSFB传输系统，可能包括有机阴离子运输 在顶端膜上的多肽（燕麦）和多药相关蛋白（MRP）处的多肽（MRP） 基底膜。我们假设燕麦介导运输中的第一个和限速步骤 跨BCSFB的结构多样化的两亲性OA，并且燕麦和MRP的表达和活性 在BCSFB处由衰老调节。该应用程序的目标是确定功能特征 在BCSFB两亲的OA运输系统中，定义了OATP1A转运蛋白在BCSFB运输中的作用，并且 探索BCSFB的转运蛋白表达和功能的年龄依赖性变化。提出的研究 将在BCSFB和 为未来的研究铺平道路，以研究BCSFB转运蛋白和衰老对CNS药物的影响 处置，药代动力学和药效学。