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Quantifying Axon Growth in Complex Environments

量化复杂环境中的轴突生长

基本信息

批准号：
7928211
负责人：
Diane Hoffman-Kim
金额：
$ 30.26万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7928211
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

项目摘要

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.

项目概述：我们的长期目标是双重的：阐明损伤后轴突引导的细胞和分子机制，以及开发支持和增强轴突生长的生物材料平台。我们的工作假设是，多种促进生长的线索的结合将使轴突生长克服局部抑制环境（即神经胶质疤痕），形成损伤后。为了验证这一假设，需要制造一个新的物理平台来研究神经元的生长。该平台将(1)以可控和可量化的方式提供促进生长的信号组合；以及(2)提供一种测试刺激环境与抑制环境的方法。这些平台将使创新实验成为可能，这些实验将首次测试引导线索的组合如何在抑制环境中促进轴突生长。NIBIB的使命是通过促进生物工程的基础发现、设计和发展来改善健康，我们的目标是将轴突的生长和方向与刺激和抑制线索的特定数量和比例联系起来，从而为神经再生的新策略奠定基础。这项创新的多学科提案结合了首席研究员在神经元发育、再生和生物材料方面的互补专业知识，以及电化学、微制造和表面表征方面的联合研究员，以制造一个能够提供精确数量的生物引导线索和电刺激的平台（目标1）。目的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）是否在促进神经突生长方面具有协同作用。目的3侧重于确定特定的刺激引导线索是否可以促进神经突生长以克服抑制环境（即硫酸软骨素蛋白聚糖）。通过药物抑制剂和激光失活方法，我们将确定整合素和trk受体以及聚集在微管细胞骨架上的下游激酶如何解释多种指导信号。这些研究结果将通过提供复杂环境下轴突生长需求的更全面的知识，推动神经再生生物材料领域的发展。公共卫生相关性：神经损伤后不能再生，目前的医学实践无法有效地操纵神经再生过程。提出的研究试图通过量化单个和组合的引导线索如何在抑制环境（如神经损伤部位）中促进轴突生长来解决这个问题。