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：
7545241
负责人：
Andrea Lynn Johnstone
金额：
$ 3.1万
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/7545241
关键词：
Affect Affinity Chromatography Aftercare Animal Model Astrocytes Axon Behavior Binding Biological Assay Chondroitin Sulfate Proteoglycan Cicatrix Class Cyclic AMP DNA Microarray Chip DNA Microarray format 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 in vivo in vivo regeneration inhibitor/antagonist insight interest novel novel therapeutics prevent receptor relating to nervous system research study rho small molecule libraries success time use

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）：拟议研究的目的是澄清导致中枢神经系统（CNS）轴突再生失败的信号事件，这种现象会导致瘫痪和术后功能恢复缺乏。脊髓损伤（SCI）。研究表明，髓鞘碎片和硫酸软骨素蛋白聚糖（CSPG）等神经胶质衍生分子构成了轴突再生的主要障碍。人们对这些分子如何抑制损伤后轴突生长知之甚少，但一些研究表明它们可能通过常见机制发出信号。显然，需要识别这些汇聚信号“节点”并利用它们来开发新的 SCI 疗法。为了实现这一目标，拟议的实验将重点确定四种新型化合物的作用机制，这些化合物是在高内涵化学遗传学筛选中鉴定出的，它们能够克服培养神经元中的两类神经胶质衍生抑制剂。令人兴奋的是，这四种化合物不仅能够深入了解参与再生抑制的复杂信号通路，而且还将在中枢神经系统再生失败的动物模型中进行测试，以确定它们用于治疗 SCI 的潜力。这项研究将使我们了解为什么神经连接在脊髓创伤后无法再生和重塑，从而为制定针对瘫痪的针对性治疗策略提供基础。这些研究不仅会让人们对神经元再生失败的机制有更深入的了解，而且还可能直接导致一种新型脊髓损伤治疗方法的开发，这种治疗方法在初步研究中已显示出希望。