Mechanisms Underlying Inhibition of Regeneration in CNS Neurons

中枢神经系统神经元再生抑制的机制

• 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
• 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

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）：拟议研究的目的是阐明导致中枢神经系统（CNS）轴突再生失败的信号事件，这种现象导致脊髓损伤（SCI）后瘫痪和缺乏功能恢复。研究表明，神经胶质衍生分子，如髓磷脂碎片和硫酸软骨素蛋白聚糖（CSPGs）构成了轴突再生的主要障碍。对于这些分子如何在损伤后抑制轴突生长知之甚少，然而一些研究表明它们可能通过共同的机制发出信号。显然，有必要识别这些趋同的信号“节点”，并利用它们来开发新的脊髓损伤治疗方法。为了实现这一目标，拟议的实验将侧重于确定四种新化合物的作用机制，这些化合物在高含量化学遗传学筛选中被鉴定出来，它们有能力克服培养神经元中两类胶质源性抑制剂。令人兴奋的是，这四种化合物不仅有能力深入了解涉及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脊髓损伤的潜力。本研究将使我们了解创伤性脊髓损伤后神经连接无法再生和改造的原因，从而为制定有针对性的麻痹治疗策略提供依据。这些研究不仅将导致对神经元再生失败机制的更深入的理解，而且还可能直接导致脊髓损伤新疗法的发展，这在初步研究中显示出希望。