Diffusion of Substances Through the Brain

物质通过大脑的扩散

• 批准号: 6639419
• 负责人: CHARLES NICHOLSON
• 金额: $ 37.8万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639419
• 关键词: autoradiography; cerebellum; computer simulation; diffusion; extracellular; extracellular matrix; hippocampus; laboratory rat; macromolecule; magnetic resonance imaging; mesencephalon

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.

描述（改编自申请人的摘要）：本研究的中心假设 应用是大脑细胞外空间（ECS）中的大分子扩散 受分子构型、局部结构、细胞外 矩阵和总体流量。 我们将使用集成光学成像 (IOI) 技术，该技术由 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， 使用离子选择性测量四甲基铵离子的浓度 微电极。上次融资期间的硬件和软件开发 期间，这两种技术都得到了极大的提高。大鼠脑切片将是 主要准备工作，但顾问将提供体内数据。有四个 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？我们已经证明一些大的球状分子会扩散 与相似分子量的线性聚合物非常不同。我们将 分析几种新大分子的扩散行为，然后改变 通过渗透操作和使用模仿的切片制剂进行 ECS 缺血以确定 ECS 大小和分子大小之间的关系。 目标 2. 大脑结构在多大程度上引导物质？有脑子吗 结构通道物质优先沿一个方向而不是 另一种（各向异性）或对物质的运动造成局部障碍 （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，我们将 能够解决这个重要但困难的问题。 目标 4. ECS 中的物料运输中的散装流量有多重要？大部分 流动可以使物质沿特定方向长距离移动，但是 缺乏确凿的证据。 Abbott 博士（顾问，伦敦）有新的数据和 我们有先进的图像分析软件，所以我们会尽力解决这个问题 长期存在的问题。开发的模型解决了总体流的起源 作者：Patlak 博士（石溪顾问）。 该应用程序专注于基础研究，特别重要的是 体积传输，但许多结果将与临床相关 问题，特别是药物输送。