Mechanisms Underlying Inhibition of Regeneration in CNS Neurons

描述(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，这是一种导致脊髓损伤(SCI)后瘫痪和缺乏功能恢复的现象。研究表明，髓鞘碎片和硫酸软骨素蛋白多糖(CSPGs)等神经胶质来源的分子构成了轴突再生的主要障碍。关于这些分子如何抑制损伤后轴突的生长，人们知之甚少，但一些研究表明，它们可能通过共同的机制发出信号。显然，有必要识别这些汇聚的信号“节点”，并利用它们来开发治疗脊髓损伤的新疗法。为了实现这一目标，拟议的实验将集中在确定四种新化合物的作用机制，这些化合物是在高含量的化学遗传学筛选中确定的，它们能够在培养的神经元中克服这两类神经胶质衍生抑制物。令人兴奋的是，这四个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，以确定它们作为脊髓损伤治疗的潜力。这项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重建的原因，从而为制定针对瘫痪的靶向治疗策略提供依据。这些研究不仅将在智力上更好地理解神经元再生失败的机制，而且还可能直接导致开发一种新的脊髓损伤治疗方法，这已在初步研究中显示出希望。

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.