NEURONAL PATHFINDING ON MODIFIED PROTEOGLYCANS

修饰蛋白聚糖的神经元寻路

基本信息

批准号：
7662258
负责人：
VLADIMIR HLADY
金额：
$ 41.66万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7662258
关键词：
Adhesives Adult Affect Afferent Neurons Age Animal Model Animals Area Astrocytes Award Axon Beds Behavior Binding Biocompatible Materials Biological Biological Assay Biological Models Biology Biomedical Engineering Biomimetics Brain Carbohydrates Cell Transplantation Cell membrane Cells Chondroitin Sulfates Cicatrix Cues Data Delaware Development Devices Engineering Environment Enzyme Tests Enzymes Exposure to Extracellular Matrix Extracellular Matrix Proteins Family Fibronectins Future Glycosaminoglycans Goals Grant Growth Health Care Costs Heparitin Sulfate Human In Vitro Injury Integrins Keratan Sulfate Knowledge Laminin Laminin Receptor Length Ligands Maps Masks Mediator of activation protein Membrane Methodology Methods Microglia Microscopic Microscopy Modeling Modification Molecular Natural regeneration Nature Nerve Nerve Regeneration Nervous system structure Neural Pathways Neuraxis Neurites Neurons Neurosciences Oligosaccharides Operative Surgical Procedures Patients Pattern Peptides Performance Physiological Play Process Proteins Proteoglycan Recombinants Research Research Personnel Resolution Rest Role Route Side Signal Transduction Spatial Distribution Spinal Ganglia Structure Surface Synthesis Chemistry Techniques Technology Testing Time Tissue Engineering Tissues To specify Transplantation Universities Utah Work Wound Healing axon growth base biomaterial compatibility biomaterial interface cohort density design functional restoration implantation injured insight macrophage man monolayer nervous system development nervous system disorder neuron development novel pre-clinical progesterone 11-hemisuccinate-(2-iodohistamine)prototype public health relevance receptor reconstruction relating to nervous system repaired research study surface coating tool

项目摘要

DESCRIPTION (provided by applicant): A major challenge remaining is the reconstruction of damaged and diseased neural pathways. Toward this end, biomaterials have been examined as bridging devices to support directed nerve outgrowth from regenerating or transplanted neurons. A fundamental challenge that remains is in understanding how to engineer bridges that are clinically useful. The proposed project builds on two observations: 1) aligned scar-like astrocytes support and direct neural outgrowth while misaligned astrocytes display minimal outgrowth even though they display similar surface cues, and 2) neurite outgrowth velocity increases when neurons encounter mixtures of permissive ligands and inhibitory proteoglycans presented in a non-physiological pattern. Based on these observations we formulated the central hypothesis of the proposed research: the local composition and spatial distribution of permissive and inhibitory ligands are the signals that underlie directed outgrowth. by astrocytes. Moreover, we believe it is possible to mimic the spatial distribution of permissive and inhibitory molecules on biomaterials, and that such surfaces could be functionally equivalent to astrocytes coated surfaces in terms of supporting and directing neuronal outgrowth. We will test this hypothesis by: (1) mapping the type and distribution of permissive and inhibitory molecules on aligned astrocyte monolayers using high-resolution microscopy to create a large area map that will aid in the design of a new biologically inspired bridging surface. By designing novel biomimetic structures and interfaces presenting permissive and inhibitory molecules with controlled local composition and spatial distribution we will study how such signals on sub-micrometer length-scales influence axonal outgrowth. (2) We propose to study the role(s) that carbohydrates moieties of the three major proteoglycan families play on directing axonal outgrowth using the novel biomimetic structures as test beds. This will be accomplished using two different routes: using (a) enzymatically modified proteoglycans, or (b) glycosaminoglycans re-assembled from oligosaccharide units synthesized from a precursor using recombinant enzymes. Both types of modifications (a) and (b) then will be tested using axonal outgrowth assays. Finally, (3) we will examine the biomimetic structure under conditions likely encountered following implantation in patients, by using a model system that exposes these surfaces to resting and activated macrophages isolated from CNS. PUBLIC HEALTH RELEVANCE: Among the most debilitating and costly human ailments are injuries and diseases of the nervous system. They affect millions of people in the US and represent a large part of the total national health care cost. Currently there are a limited number of available therapies, none of which restore function to injured neurons of the central nervous system. Numerous studies in animals and man strongly suggest that restorative therapies based on cell transplantation are feasible. A major challenge remains is the reconstruction of damaged and diseased neural pathways. Toward this end, biomaterials have been examined as bridging devices to support directed nerve outgrowth from regenerating neurons. A fundamental challenge involves understanding how to engineer such biomaterial bridges. The proposed project's main objective is to evaluate the construction of such bridging devices based on astrocyte-derived distribution of modified neuron-directing molecules from the nervous system.

描述（由申请人提供）：剩下的主要挑战是重建受损和患病的神经途径。为此，已将生物材料作为桥接装置进行了研究，以支持重生或移植神经元的定向神经产物。剩下的一个基本挑战是理解如何设计临床上有用的桥梁。 The proposed project builds on two observations: 1) aligned scar-like astrocytes support and direct neural outgrowth while misaligned astrocytes display minimal outgrowth even though they display similar surface cues, and 2) neurite outgrowth velocity increases when neurons encounter mixtures of permissive ligands and inhibitory proteoglycans presented in a non-physiological pattern.基于这些观察结果，我们制定了拟议研究的中心假设：允许和抑制性配体的局部组成和空间分布是指导生长的信号。由星形胶质细胞。此外，我们认为有可能在生物材料上模仿允许和抑制性分子的空间分布，并且这种表面在功能上可能等于星形胶质细胞涂层的表面，以支撑和指导神经元出现。我们将通过：（1）绘制使用高分辨率显微镜在对齐星形胶质细胞单层对允许和抑制分子的类型和分布进行测试，以创建一个大面积图，以帮助设计新的生物学启发的桥梁。通过设计具有控制局部组成和空间分布的允许和抑制分子的新型仿生结构和界面，我们将研究这些信号在亚微米长度尺度上如何影响轴突的生长。（2）我们建议研究三个主要蛋白聚糖家族的碳水化合物在使用新型仿生结构作为测试床的指导轴突生长方面发挥作用的作用。这将使用两种不同的途径来完成：使用（a）酶修饰的蛋白聚糖，或（b）使用重组酶从前体合成的寡糖单位重新组装从寡糖单位重新组装的糖胺聚糖。然后，两种类型的修改（a）和（b）将使用轴突出生测定测试。最后，（3）我们将通过使用模型系统将这些表面暴露于从CNS中分离出的静息和激活的巨噬细胞来检查患者植入后可能遇到的仿生结构。公共卫生相关性：最衰弱和昂贵的人类疾病是神经系统的伤害和疾病。它们影响美国数以百万计的人，代表了国家保健总成本的很大一部分。目前，可用的疗法数量有限，其中没有一个恢复功能为中枢神经系统的受伤神经元。对动物和人类的大量研究强烈表明基于细胞移植的恢复性疗法是可行的。一个主要的挑战仍然是重建受损和患病的神经途径。为此，已经将生物材料作为桥接装置进行了研究，以支持重生神经元的定向神经产物。一个基本挑战涉及了解如何设计这种生物材料的桥梁。拟议的项目的主要目标是根据星形胶质细胞衍生的神经元导向分子的分布来评估这种桥接设备的构建。