Mechanisms Underlying Inhibition of Regeneration in CNS Neurons

中枢神经系统神经元再生抑制的机制

基本信息

批准号：
7888145
负责人：
Andrea Lynn Johnstone
金额：
$ 2.12万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888145
关键词：
Affect Affinity Chromatography Aftercare Animal Model Astrocytes Axon Behavior Binding Biological Assay Chondroitin Sulfate Proteoglycan Cicatrix Cyclic AMP DNA Microarray Chip Development Epidermal Growth Factor Receptor Event Failure Genetic Screening Goals Growth Inflammatory Response Injury Lead Lesion Mediating Microarray Analysis Microscopy Microtubules Modeling Molecular Molecular Target Myelin Natural regeneration Neuraxis Neurites Neurons Optics Paralysed Pathway interactions Population Protein Kinase C Protein Microchips Proteins Recovery of Function Research Retinal Ganglion Cells Sensory Signal Pathway Signal Transduction Spinal Spinal Cord Spinal cord injury System Testing Therapeutic Tissues Triazines axon regeneration base chemical genetics dorsal column efficacy testing flexibility in vivo in vivo regeneration inhibitor/antagonist insight interest novel novel therapeutics prevent receptor regenerative relating to nervous system research study rho small molecule libraries success time use treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The objective of the proposed studies is to clarify the signaling events that are responsible for the failure of axon regeneration in the central nervous system (CNS), a phenomenon which leads to paralysis and a lack of functional recovery after spinal cord injury (SCI). Studies have shown that glial derived molecules such as myelin debris and chondroitin sulfate proteoglycans (CSPGs) comprise the major barrier to axon regeneration. Relatively little is known about how these molecules inhibit axon outgrowth after injury, however some studies suggest that they may signal through common mechanisms. Clearly there is a need to identify these convergent signaling "nodes" and to exploit them in the interest of developing novel therapeutics for SCI. To accomplish this goal, the proposed experiments will focus on identifying the mechanism of action of four novel compounds, identified in a high content chemical genetics screen, that have the ability to overcome both classes of glial derived inhibitors in cultured neurons. Excitingly, these four compounds not only have the ability to lend insight into the complicated signaling pathways involved in regeneration inhibition, but will also be tested in animal models of CNS regenerative failure in order to determine their potential to be used as treatments for SCI. This research will allow us to understand why neural connections are unable regrow and reform after traumatic spinal cord injury, thus providing a basis for the development of targeted treatment strategies for paralysis. Not only will these studies lead to a greater intellectual understanding of the mechanisms underlying the failure of neuronal regeneration, but may also directly lead to the development of a novel therapeutic for SCI, which has shown promise in preliminary studies.

描述（由申请人提供）：拟议的研究的目的是阐明导致轴突再生在中枢神经系统（CNS）中失败的信号事件，这是一种导致麻痹和脊髓损伤后功能恢复（SCI）缺乏功能恢复的现象。研究表明，神经胶质衍生的分子，例如髓磷脂碎片和硫酸软骨蛋白蛋白聚糖（CSPGS）构成了轴突再生的主要障碍。对于这些分子如何抑制损伤后轴突的生长，相对较少了解，但是一些研究表明它们可能通过常见机制发出信号。显然，有必要识别这些收敛信号“节点”，并为了开发SCI的新型治疗剂而利用它们。为了实现这一目标，提出的实验将集中于确定在高含量化学遗传学筛查中鉴定出的四种新型化合物的作用机理，这些化合物在培养的神经元中都具有克服两类的神经胶质抑制剂的能力。令人兴奋的是，这四种化合物不仅能够深入了解与再生抑制有关的复杂信号通路，而且还将在CNS再生失效的动物模型中进行测试，以确定其潜力用作SCI的治疗方法。这项研究将使我们能够理解为什么神经联系在创伤性脊髓损伤后无法再生和改革，从而为制定靶向治疗策略的制定提供了基础。这些研究不仅会导致对神经元再生失败的机制有更深入的智力理解，而且还可能直接导致SCI新型治疗性的发展，这在初步研究中表现出了希望。