Diffusion of Substances Through the Brain

描述(改编自申请者的摘要)：本研究的中心假设 应用是大分子在脑细胞外空间的扩散 受分子构型、局部结构、细胞外 矩阵和块流。 我们将使用集成光学成像(IOI)技术支持 TMA+法。在IOI方法中，一团扩散的荧光大分子 用复合显微镜成像并量化。在TMA+方法中， 用离子选择法测四甲基铵离子浓度 微电极。上次资助期间的硬件和软件开发 时期极大地改进了这两种技术。大鼠脑片将成为 主要准备工作，但顾问将提供活体数据。一共有四个 具体目标： 目标1.ECS体积如何与大分子的形状和大小相互作用 来影响扩散吗？我们已经证明了一些大的球状分子扩散 与分子量相近的线型聚合物非常不同。我们会 分析了几种新的大分子的扩散行为，然后改变了 通过渗透操作和通过使用模拟的切片制剂 以确定ECS大小和分子大小之间的关系。 目标2.大脑结构通道有多少物质？大脑呢？ 优先在一个方向上构造通道物质，而不是 另一种(各向异性)或对物质运动构成局部障碍 (异质性)？ 目的3.细胞外基质对扩散有多大影响？实际的 细胞外基质的数量和分布尚不清楚。拥有 确定各种其他因素如何影响目标1-2中的扩散 有能力解决这一重要但困难的问题。 目标4.散装物流在ECS的材料运输中有多重要？散装 流动可以在很长的距离内沿特定方向移动物质，但 目前还缺乏确凿的证据。Abbott博士(伦敦顾问)有了新的数据和 我们有复杂的图像分析软件，所以我们将努力解决这个问题 这个问题由来已久。在开发的一个模型中讨论了体流的来源 帕特拉克博士(石溪咨询公司)。 这项申请的重点是基础研究，对 体积传播，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.