Diffusion of Substances Through the Brain

物质通过大脑的扩散

• 批准号: 8013815
• 负责人: CHARLES NICHOLSON
• 金额: $ 36.23万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013815
• 关键词: Accounting; Adult; Affect; Area; Binding; Biological Assay; Brain; Brain region; Carbohydrates; Cells; Cerebellum; Cerebrospinal Fluid; Chemicals; Chronic Disease; Complex; Computer Simulation; Computer software; Convection; Corpus Callosum; Data; Development; Diffuse; Diffusion; Diffusion Magnetic Resonance Imaging; Environment; Excision; Extracellular Matrix; Extracellular Space; Fiber; Fibroblast Growth Factor 2; Fluorescent Dyes; Goals; Growth Factor; Health; Image; Imaging Techniques; Injection of therapeutic agent; Investigation; Ions; Kinetics; Label; Lactoferrin; Literature; Magnetic Resonance; Measurement; Measures; Methods; Modeling; Molecular; Neurosciences; Parkinson Disease; Pattern; Pharmaceutical Preparations; Play; Process; Property; Proteins; Publishing; Rattus; Resolution; Role; Shapes; Signal Transduction; Site; Slice; Solutions; Source; Structure of molecular layer of cerebellar cortex; Supercomputing; Techniques; Therapeutic; Therapeutic Agents; Time; Tissues; Viscosity; Work; base; brain cell; brain tissue; brain volume; extracellular; imaging modality; improved; insight; light scattering; neglect; neurotrophic factor; optical imaging; pressure; programs; public health relevance; research study; simulation; small molecule; tetramethylammonium; tool; vector; white matter

DESCRIPTION (provided by applicant): The long term goal of this work is to understand how substances diffuse in the brain extracellular space (ECS). The ECS is the narrow gap (about 30 - 50 nm) that separates one cell from another in brain. This gap contains a solution that resembles cerebrospinal fluid and an extracellular matrix made up of complex long chain carbohydrate molecules. This project focuses on the role of the extracellular matrix in hindering and patterning diffusion. The major tool for this work will be Monte Carlo simulation using the MCell software and this will be supported by experiments using the integrative optical imaging (IOI) method to measure extracellular diffusion in rat brain slices. The project has three Aims. The first Aim is to determine the origin of the extracellular components of anisotropic diffusion arising from aligned fiber bundles. Such bundles play a major role in the magnetic resonance technique of diffusion tensor imaging. Measurements of the extracellular diffusion of the probe ion tetramethylammonium have been made previously in three axes in both corpus callosum and in the molecular layer of the cerebellum. These measurements reveal paradoxes in the component values in both regions that suggest a more complex relation between geometry and diffusion than hitherto assumed. Modeling supported by experiments will determine the role of extracellular matrix and geometrical factors in accounting for the discrepancies. The second Aim will determine how the diffusion of growth factors is modified by binding to extracellular matrix. Growth factors are endogenous proteins that are potent agents that promote brain cell plasticity in adults and are essential during development. They diffuse in the ECS and are being trialed as therapeutic agents to relieve Parkinson's Diseases and other chronic illnesses. The extracellular matrix binds growth factors and may act as a local storage site for them and these processes are modified by the diffusion properties of the ECS geometry, however there is little quantitative understanding of these processes. Modeling and experiments with the FGF-2 growth factor will determine combinations of binding and diffusion and geometric parameters that will account for observed data. The third Aim is to improve the resolution of the IOI method which is based on imaging a cloud of diffusing molecules that are made visible by prior attachment of a fluorescent dye. Presently, the source of molecules is achieved by pressure injecting a small amount from a micropipette but in this project a highly controlled iontophoretic source will be developed to release the molecules. In some conditions, light scattering may limit the resolution of IOI and a correction for this will be formulated. PUBLIC HEALTH RELEVANCE: This project focuses on the role of the extracellular matrix (an entanglement of long complex molecules) in hindering diffusion of substances, including potential drugs, as they move in the narrow spaces between brain cells. Diffusion studies in fiber-rich brain regions will improve the basis for the magnetic resonance technique of diffusion tensor imaging (DTI) and investigations on the diffusion and binding of growth factors will facilitate therapeutic delivery to the brain. Development of an imaging technique for fluorescent molecules will provide a relatively inexpensive method for measuring diffusion of drugs in brain tissue.

描述（由申请人提供）：这项工作的长期目标是了解物质如何在脑细胞外间隙（ECS）中扩散。ECS是将大脑中的一个细胞与另一个细胞分开的狭窄间隙（约30 - 50纳米）。该间隙包含类似于脑脊液的溶液和由复杂的长链碳水化合物分子组成的细胞外基质。这个项目的重点是细胞外基质在阻碍和模式化扩散中的作用。这项工作的主要工具将是蒙特卡罗模拟使用MCell软件，这将得到实验的支持，使用集成光学成像（IOI）的方法来测量细胞外扩散在大鼠脑切片。该项目有三个目标。第一个目标是确定由对齐的纤维束产生的各向异性扩散的细胞外成分的起源。这种束在磁共振扩散张量成像技术中起着重要作用。探针离子四甲基铵的细胞外扩散的测量先前已经在胼胝体和小脑的分子层中的三个轴中进行。这些测量揭示了悖论的组件值在这两个地区，这表明几何形状和扩散之间的关系比迄今为止假设的更复杂。由实验支持的建模将确定细胞外基质和几何因素在解释差异中的作用。第二个目标将确定生长因子的扩散是如何通过与细胞外基质结合而改变的。生长因子是内源性蛋白质，是促进成人脑细胞可塑性的强效因子，在发育过程中至关重要。它们在ECS中扩散，并被用作治疗剂来缓解帕金森病和其他慢性疾病。细胞外基质结合生长因子，并可能作为他们的本地存储网站，这些过程被修改的ECS几何形状的扩散特性，但是很少有定量的了解这些过程。FGF-2生长因子的建模和实验将确定结合和扩散的组合以及几何参数，这些参数将解释观察到的数据。第三个目的是提高IOI方法的分辨率，该方法基于对通过事先附着荧光染料而变得可见的扩散分子云进行成像。目前，分子来源是通过从微量移液管中压力注射少量来实现的，但在本项目中，将开发高度受控的离子电渗源来释放分子。在某些情况下，光散射可能会限制IOI的分辨率，并将制定对此的校正。 公共卫生关系：该项目的重点是细胞外基质（长的复杂分子的缠结）在阻碍物质扩散中的作用，包括潜在的药物，因为它们在脑细胞之间的狭窄空间中移动。在纤维丰富的大脑区域的扩散研究将改善扩散张量成像（DTI）的磁共振技术的基础上，扩散和生长因子的结合的调查将促进治疗交付到大脑。荧光分子成像技术的发展将为测量药物在脑组织中的扩散提供一种相对廉价的方法。