Diffusion of Substances Through the Brain

物质通过大脑的扩散

• 批准号: 7243336
• 负责人: CHARLES NICHOLSON
• 金额: $ 33.35万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7243336
• 关键词: Address; Affect; Alcohol or Other Drugs use; Algorithms; Anions; Binding; Biogenic Amines; Biological Assay; Biophysics; Brain; Brain region; Caliber; Charge; Chemicals; Chondroitin Sulfates; Complex; Computer software; Corpus striatum structure; Custom; Data Analyses; Diffuse; Diffusion; Discrimination; Divalent Cations; Drug Delivery Systems; Environment; Enzymes; Extracellular Matrix; Extracellular Space; Future; Glycosaminoglycans; Goals; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hyaluronan; Ions; Iontophoresis; Laboratories; Lactoferrin; Length; Maintenance; Measurement; Methods; Modeling; Neocortex; Obstruction; Proteins; Proteoglycan; Quantum Dots; Range; Research Personnel; Signal Transduction; Slice; Theoretical model; Time; Tissues; Viscosity; Writing; base; brain cell; density; in vivo; interstitial; macromolecule; molecular size; nanoparticle; optical imaging; particle; programs; receptor; research study; size; stem; tetramethylammonium

DESCRIPTION (provided by applicant): The long-term goal is to understand the biophysics of substance diffusion in brain extracellular space (ECS). Biomedically, this proposal will enhance understanding of impediments to drug delivery in brain and factors that affect chemical signaling in the ECS. The ECS comprises the ensemble of narrow interstitial spaces between brain cells and harbors an extracellular matrix (ECM) of long chain glycosylated molecules. Hindrance to diffusion in the ECS is characterized by a composite parameter, the tortuosity, that includes a) increase in geometric path-length, b) dead-space microdomains, c) obstruction and interstitial viscosity, d) specific binding to ECM and e) nonspecific interaction with fixed negative charges on the ECM. These factors will be explored through the diffusion of substances using integrative optical imaging of fluorescent macromolecules combined with realtime iontophoresis of tetramethylammonium and other ions both in vivo and in brain slices. Aim 1: What is the largest molecule or particle that can traverse the ECS? Preliminary experiments show that macromolecules with 40 nm diameter can diffuse in vivo. A further range of molecular sizes will be explored in normal and osmotically modified ECS. Aim 2: How much does specific ECM binding hinder diffusion of biologically important molecules? Diffusion of the naturally occurring model protein, lactoferrin, will assay specific binding with heparan sulfate proteoglycans of the ECM. Aim 3: Is there charge discrimination in the ECS? This aim will study the non-specific interaction of diffusing mono- and multivalent ions and biogenic amines with the fixed negative charges of the ECM. Aim 4: Model dead-space microdomains, binding and charge interaction and unify software. Models and algorithms for data analysis will be developed and the custom software unified to facilitate outside users

描述（由申请人提供）：长期目标是了解脑细胞外空间（ECS）中物质扩散的生物物理学。从生物医学角度来看，该提案将增强对大脑药物输送障碍和影响 ECS 化学信号传导因素的理解。 ECS 由脑细胞之间狭窄的间隙空间组成，并含有长链糖基化分子的细胞外基质 (ECM)。 ECS 中扩散阻碍的特征是复合参数，即曲折度，包括 a) 几何路径长度的增加，b) 死腔微域，c) 阻塞和间隙粘度，d) 与 ECM 的特异性结合，以及 e) 与 ECM 上固定负电荷的非特异性相互作用。这些因素将通过使用荧光大分子的综合光学成像结合体内和脑切片中四甲基铵和其他离子的实时离子电渗疗法的物质扩散来探索。 目标 1：能够穿过 ECS 的最大分子或粒子是什么？初步实验表明，直径40 nm的大分子可以在体内扩散。将在正常和渗透改性 ECS 中探索进一步的分子大小范围。 目标 2：特定的 ECM 结合对重要生物学分子的扩散有多大阻碍？ 天然存在的模型蛋白乳铁蛋白的扩散将测定与 ECM 的硫酸乙酰肝素蛋白聚糖的特异性结合。 目标3：ECS是否存在收费歧视？该目标将研究扩散的单价和多价离子以及生物胺与 ECM 的固定负电荷的非特异性相互作用。 目标 4：对死空间微域、结合和电荷相互作用进行建模并统一软件。将开发数据分析的模型和算法，并统一定制软件以方便外部用户