Reactivating atrophied Schwann cells for long-distance nerve regeneration

 描述(由申请人提供)：周围神经损伤在美国很常见，每年影响25万人。即使在手术修复后，完全恢复也是罕见的；&gt；90%的患者患有长期的运动和感觉障碍。功能恢复很差，因为周围神经很少长距离再生。远距离再生失败的主要原因是雪旺细胞在损伤后随着时间的推移失去了支持轴突再生的能力。目前还没有可用的治疗方法来鼓励雪旺细胞继续促进再生，甚至还不知道雪旺细胞萎缩是否可以预防或逆转。我们最近发现，诱导性活性ErbB2受体酪氨酸激酶(CaErbB2)的表达显著增强了雪旺细胞的再生促进能力。此外，我们的初步结果表明，caErbB2能够使慢性失神经、萎缩的雪旺细胞扩大、分裂、迁移和延长过程。值得注意的是，我们几乎没有观察到对未受损伤的神经支配的雪旺细胞的影响，这表明治疗性的caErbB2几乎没有非靶点的影响。在R21的应用中，我们建议进一步探索caErbB2逆转雪旺细胞萎缩的可能性，并确定它是否促进长距离轴突再生。我们将结合传统的解剖学和功能分析，以及先进的技术，如可诱导的荧光转基因小鼠、体内成像和透明，以确定：(1)诱导表达caErbB2是否重新激活慢性失神经神经中萎缩的雪旺细胞，以及(2)是否由caErbB2重新激活的雪旺细胞促进轴突再生。这些概念验证实验将提供关键数据，证明更大规模的拨款申请是合理的，该申请将调查caErbB2引起的信号级联反应，确定其关键效应者，定义caErbB2疗效的治疗窗口，并开发一种可用于治疗的增强ErbB2信号的方法。因此，这项拟议的工作有可能为开发一种有效的治疗方法奠定坚实的基础，使患者能够进行远程神经再生。

 DESCRIPTION (provided by applicant): Peripheral nerve injuries are common and affect >250,000 individuals annually in the US. Full recovery is rare even after surgical repair; >90% of patients suffer long-term motor and sensory deficits. Functional recovery is poor because peripheral nerves rarely regenerate over long distances. Long-distance regeneration fails largely because Schwann cells lose their ability to support axon regeneration over time after injury. No therapy is currently available to encourage Schwann cells to continue to promote regeneration, and it is not even known whether Schwann cell atrophy can be prevented or reversed. We have recently discovered that induced expression of constitutively active ErbB2 receptor tyrosine kinase (caErbB2) dramatically enhances the regeneration-promoting capability of Schwann cells. Moreover, our preliminary results show that caErbB2 enables chronically denervated, atrophied Schwann cells to enlarge, divide, migrate and extend processes. Notably, we have observed few, if any, effects on innervated Schwann cells that were spared injury, suggesting that therapeutic caErbB2 would have few off-target effects. In this R21 application, we propose to explore further the possibility that caErbB2 reverses Schwann cell atrophy and determine whether it promotes long-distance axon regeneration. We will combine conventional anatomical and functional analyses with advanced techniques such as inducible fluorescent transgenic mice, in vivo imaging and CLARITY, to determine: (1) if induced expression of caErbB2 reactivates atrophied Schwann cells in chronically denervated nerve, and (2) if the Schwann cells reactivated by caErbB2 promote axon regeneration. These proof-of- concept experiments will provide critical data to justify a larger grant application that will investigate the signalin cascades evoked by caErbB2, identify its key effectors, define the therapeutic window of caErbB2 efficacy and develop a therapeutically applicable method of boosting ErbB2 signaling. The proposed work therefore has the potential to establish a strong foundation for developing a potent treatment that enables long- distance nerve regeneration in patients.