Diffusion of Substances Through the Brain

描述（改编自申请人摘要）：本研究的中心假设 应用是脑细胞外间隙（ECS）中的大分子扩散， 是由分子结构，局部结构，细胞外 基质和整体流动。 我们将使用集成光学成像（IOI）技术支持的B y TMA+方法。在IOI方法中，荧光大分子的扩散云 用复合显微镜成像并定量。在TMA+方法中， 四甲基铵离子的浓度使用离子选择性 微电极上一次资助期间的硬件和软件开发 这两种技术都有很大的改进。老鼠的大脑切片将是 主要制备，但顾问将提供体内数据。有四 具体目标： 目标1. ECS体积如何与大分子的形状和尺寸相互作用 影响扩散吗我们已经证明了一些大的球状分子扩散 与类似分子量的线性聚合物非常不同。我们将 分析了几种新的大分子的扩散行为， 通过渗透操作和使用模拟 以确定ECS大小与分子大小之间的关系。 目标2.大脑结构有多少通道物质？大脑是否 结构化通道物质优先在一个方向，而不是 另一个（各向异性）或对物质的运动构成局部障碍 （不均匀性）？ 目标3。细胞外基质对扩散的影响有多大？实际 细胞外基质的数量和分布还远不清楚。具有 我们将在目标1-2中确定各种其他因素如何影响扩散， 有能力解决这个重要而困难的问题。 目标4。大流量在ECS中的材料运输中有多重要？散装 流动可以使物质沿特定方向长距离移动， 缺乏确凿的证据。Abbott博士（顾问，伦敦）有新的数据， 我们有先进的图像分析软件，所以我们将尝试解决这个问题 长期的问题。的起源散装流是解决在模型开发 作者：Patlak博士（斯托尼布鲁克顾问）。 这项申请的重点是基础研究，特别是对 体积传输，但许多结果将与临床相关 问题，特别是药物输送。

DESCRIPTION (Adapted from applicant's abstract): The central hypothesis of this application is that macromolecular diffusion in brain extracellular space (ECS) is controlled by molecular configuration, local architecture, the extracellular matrix, and bulk flow. We will use the Integrative Optical Imaging (IOI) technique support b y the TMA+ method. In the IOI method, a diffusing cloud of fluorescent macromolecules is imaged with a compound microscope and quantified. In the TMA+ method, the concentration of tetramethylammonium ions is measured using ion-selective microelectrodes. Hardware and software developments during the last funding period have greatly improved both techniques. Rat brain slices w3ill be the main preparation but a consultant will provide in vivo data. There are four Specific Aims: Aim 1. How does ECS volume interact with the shape and size of a macromolecule to affect diffusion? We have shown that some large globular molecules diffuse very differently from linear polymers of similar molecular weight. We will analyze the diffusion behavior of several new macromolecules and then alter the ECS by osmotic manipulation and by using a slice preparation that mimics ischemia to determine the relation between ECS size and molecular size. Aim 2. How much does brain architecture channel substances? Does brain structure channel substances preferentially in one direction rather than another (anisotropy) or pose local barriers to the movement of substances (inhomogeneity)? Aim 3. How much does the extracellular matrix affect diffusion? The actual amount and distribution of the extracellular matrix are far from clear. Having established how various other factors affect diffusion in Aims 1-2 we will be in a position to tackle this important but difficult problem. Aim 4. How important is bulk flow in the transport of material in the ECS? Bulk flow could move substances in a specific direction over long distances but conclusive evidence is lacking. Dr Abbott (consultant, London) has new data and we have sophisticated image analysis software, so we will try to settle this long-standing issue. The origin of bulk flow is addressed in a model developed by Dr Patlak (consultant, Stony Brook). This application is focused on basic research with especial importance for volume transmission but many of the results will be relevant to clinical issues, especially drug delivery.