Combinatorial approaches to maximize axon regeneration after spinal cord injury

描述(申请人提供)：由于成人的高度抑制环境，创伤后中枢神经系统中的轴突不易再生。 中枢神经系统，尤其是在受伤之后。此外，成年轴突通常缺乏内在的生长潜力，因此不能维持在一些受损轴突中观察到的初始萌发。此外，随着时间的推移，受损的轴突往往会从受损的地方更远地回缩，这使得修复变得更加困难。因此，对于成功的解剖再生和功能恢复来说，组合的方法是必要的。许多在发育中起重要作用的轴突引导分子仍然存在于成人中枢神经系统中，仅次于神经系统。还有一些在受伤后被重新诱导。WNT是控制沿着发育中的脊髓的嘴-尾轴的一些轴突的路径寻找的引导线索。WNT通过其七跨跨膜受体Frizzleds吸引上升轴突，并通过脊髓中不同的跨膜受体Ryk排斥其他轴突。我们的研究表明，重新诱导的Wnt信号系统调节受损的成年中枢神经系统中轴突的生长锥体。RYK介导的Wnt排斥引起损伤的皮质脊髓束轴突的收缩/死亡，并限制本体感觉轴突的再生潜力，即使在周围支损伤后，挤压周围支也能增强感觉轴突中央支的生长状态。这笔赠款测试了是否可以通过组合方法进行更有效的再生。我们将测试结合Wnt信号处理和PTEN缺失是否可以进一步增强条件性损伤的再生潜力。

DESCRIPTION (provided by applicant): Axons in the central nervous system do not regenerate readily after traumatic injury because of the highly inhibitory environment of the adult central nervous system especially following injury. In addition, adult axons generally lack intrinsic growth potential and therefore cannot sustain the initial sprouting observed in some of the injured axons. Furthermore, injured axons often retract further back from where they are lesioned over time, making repair even more challenging. Therefore, combinatorial approaches will be necessary for successful anatomical regeneration and functional recovery. Many axon guidance molecules important in development are still present in the adult central nervous system after the nervous system. Still others are found re- induced after injury. Wnts are guidance cues that control pathfinding of a number of axons along the rostral-caudal axis of the developing spinal cord. Wnts attract ascending axons via their seven-span transmembrane receptors, Frizzleds, and repel others via a different transmembrane receptor, Ryk, in the spinal cord. Our studies showed that the re-induced Wnt signaling system regulates the growth cone of axons in the injured adult central nervous system. Ryk-mediated Wnt repulsion causes the well-known retraction/die back of injured corticospinal tract axons and limits the regenerative potential of proprioceptive sensory axons even after conditioning lesion of their peripheral branches, whereby crushing the peripheral branch enhances the growth state of the central branch of sensory axons. This grant tests whether more effective regeneration can occur by combinatorial approaches. We will test whether combining Wnt signaling manipulation and PTEN deletion can further enhance the regenerative potential of conditioning lesion.