Quantifying Axon Growth in Complex Environments

量化复杂环境中的轴突生长

• 批准号: 7629769
• 负责人: Diane Hoffman-Kim
• 金额: $ 30.61万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629769
• 关键词: Axon; Binding Sites; Biocompatible Materials; Biological; Biomedical Engineering; Cells; Chondroitin Sulfate Proteoglycan; Cicatrix; Complement; Complex; Cues; Cytoskeleton; Development; Dimensions; Electric Stimulation; Electrochemistry; Electrodes; Environment; Factor V; Film; Goals; Growth; Health; Image Analysis; Individual; Injury; Integrins; Knowledge; Lasers; Lesion; Life; Measures; Mediating; Medical; Methods; Microfabrication; Microtubules; Mission; Molecular; Natural regeneration; Nerve; Nerve Growth Factors; Nerve Regeneration; Nervous system structure; Neurites; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 1; Pathway interactions; Phosphotransferases; Population; Positioning Attribute; Principal Investigator; Problem Solving; Process; Protein Kinase; Relative (related person); Research; Research Personnel; Science; Signal Transduction; Site; Spectroscopy, Fourier Transform Infrared; Spinal Ganglia; Stimulus; Surface; Testing; Time; Video Microscopy; Western Blotting; Work; axon growth; axon guidance; base; chromophore; covalent bond; design; improved; in vitro Model; inhibitor/antagonist; innovation; laminin-1; multidisciplinary; nerve injury; neurite growth; neuron development; neuronal growth; polypyrrole; public health relevance; receptor; research study; response; voltage

DESCRIPTION (provided by applicant): Quantifying Axon Growth in Complex Environments Project Summary: Our long-term objective is twofold: to elucidate the cellular and molecular mechanisms that underlie axon guidance after injury, and to develop biomaterial platforms to support and enhance axon growth. Our working hypothesis is that the combination of multiple growth-promoting cues will enable axon growth to overcome the local inhibitory environment (i.e., glial scar) that develops post-injury. To test this hypothesis will require the fabrication of a new physical platform upon which to study neuronal growth. The platform will (1) deliver a combination of growth-promoting cues in a controllable and quantifiable manner; and (2) provide a means by which to test a stimulatory environment against an inhibitory environment. These platforms will make possible innovative experiments that will test for the first time how combinations of guidance cues promote axon growth in an inhibitory environment. Relevant to NIBIB's mission to improve health by promoting fundamental discoveries, design, and development in bioengineering, our objective is to correlate axon growth and direction to specific quantities and ratios of stimulatory and inhibitory cues, thus establishing the basis for new strategies for nerve regeneration. This innovative multidisciplinary proposal combines the complimentary expertise of the Principal Investigator in neuronal development, regeneration, and biomaterials and the Co-Investigator in electrochemistry, microfabrication, and surface characterization, to fabricate a platform capable of delivering precise quantities of both biological guidance cues and electrical stimulation (Aim 1). Aim 2 focuses on determining if specific stimulatory guidance cues (i.e., electrical stimulation, laminin-1, and nerve growth factor) are synergistic at enhancing neurite growth. Aim 3 focuses on determining if specific stimulatory guidance cues can promote neurite growth to overcome an inhibitory environment (i.e., chondroitin sulfate proteoglycans). With pharmacological inhibitors and laser inactivation approaches, we will determine how integrin and trk receptors and downstream kinases that converge on the microtubule cytoskeleton function to interpret multiple guidance cues. Results from these studies will advance the field of biomaterials for nerve regeneration by providing more comprehensive knowledge of the requirements for axon growth in complex environments. PUBLIC HEALTH RELEVANCE: Nerves fail to regenerate after injury and current medical practice is unable to manipulate effectively the process of nerve regeneration. The proposed research seeks to solve this problem by quantifying how guidance cues, both individually and in combination, promote axon growth in an inhibitory environment such as a nerve injury site.

描述（由申请人提供）：量化复杂环境中的轴突生长项目摘要：我们的长期目标是双重的：阐明受伤后轴突指导的基础的细胞和分子机制，并开发了支持和增强轴突生长的生物材料平台。 我们的工作假设是，多种增长提示的结合将使轴突生长能够克服局部抑制环境（即神经胶质疤痕）。 为了检验这一假设，将需要制造一个新的物理平台，以研究神经元生长。 该平台（1）将以可控制和可量化的方式提供促进生长提示的组合； （2）提供了一种对抑制环境测试刺激环境的方法。 这些平台将进行可能的创新实验，这将首次测试指导线索的组合如何在抑制环境中促进轴突生长。 与尼比布（Nibib）通过促进生物工程中的基本发现，设计和发展改善健康的使命相关，我们的目标是将轴突的生长和方向与刺激性和抑制性线索的特定数量和比率相关联，从而为神经再生的新策略建立了基础。 这项创新的多学科提案结合了神经元发展，再生和生物材料的主要研究者的免费专业知识，以及在电化学，微型制动和表面表征方面的共同投资者，以制造一个能够提供一个能够提供生物学指导性能刺激和电力刺激（AIL 1 AIL 1）的平台。 AIM 2侧重于确定特定的刺激引导线索（即电刺激，层粘连蛋白-1和神经生长因子）是否在增强神经突生长方面具有协同作用。 AIM 3专注于确定特定的刺激引导线索是否可以促进神经突的生长以克服抑制环境（即硫酸软骨蛋白蛋白聚糖）。 使用药理学抑制剂和激光灭活方法，我们将确定整联蛋白和TRK受体和下游激酶如何在微管细胞骨架功能上融合以解释多个指导线索。 这些研究的结果将通过对复杂环境中轴突生长的需求提供更全面的了解，从而推进神经再生的生物材料领域。 公共卫生相关性：受伤后神经无法再生，目前的医疗实践无法有效地操纵神经再生过程。 拟议的研究旨在通过量化指导线索在抑制性环境（例如神经损伤部位）中促进轴突生长，以解决该问题。