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

研究综述 脑疾病，特别是与年龄有关的神经系统疾病，构成了一个主要的公共卫生问题， 发达世界。尽管迫切需要新的和更有效的药物来治疗脑部疾病， CNS药物的开发仍然具有挑战性。CNS靶向药物要发挥其治疗作用， 穿过血脑屏障（BBB）和血-脑脊液屏障（BCSFB）， 大脑中的有效浓度。BBB和BCSFB不仅是物理屏障， 多特异性药物转运蛋白的光谱，以积极地从大脑中清除药物和其他外源性物质。的 形成BCSFB的脉络丛上皮（CPE）细胞在药物的脑清除中起重要作用， 通过CSF的分泌和溶质从CSF主动转运到血液循环中，代谢物被释放。 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 变化 开发了一种活组织成像方法， 脉络丛，以分析CPE细胞中的有机阴离子和阳离子转运过程。我们 在BCSFB的过程。此外，已知CPE细胞 在老化过程中发生变化， 目前尚不清楚这些年龄依赖性的基因是否会影响 BCSFB的运输员我们的实验室最近 初步研究 表明大的两亲性有机阴离子（OAs）从CSF侧迅速清除到血液中 毛细管侧通过高功能的BCSFB运输系统，可能由有机阴离子运输系统组成， 多药耐药相关蛋白（Mrps）位于细胞膜顶端， 基底外侧膜我们假设Oatps介导的第一个和限速步骤的运输， BCSFB中结构多样的两亲性OAs，以及Oatps和Mrps的表达和活性 在BCSFB是由老化调节的。此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Oatp 1a转运蛋白在BCSFB转运中的作用， 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的主要异生物质清除途径建立功能和机制框架， 为将来研究BCSFB转运蛋白和衰老对CNS药物的影响铺平道路 分布、药代动力学和药效学。

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.