Reactivating atrophied Schwann cells for long-distance nerve regeneration

重新激活萎缩的雪旺细胞以实现长距离神经再生

基本信息

批准号：
9134872
负责人：
YOUNG-JIN SON
金额：
$ 19.5万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9134872
关键词：
Affect American Animals Applications Grants Atrophic Axon Characteristics Chronic Clinical Data Denervation Distal Doxycycline Exploratory/Developmental Grant Foundations Genes Goals Growth Guidelines Health Human Individual Injury Investigation Label Lead Life Measures Methods Molecular Motor Mus Muscle Natural regeneration Nerve Nerve Regeneration Operative Surgical Procedures Patients Peripheral Peripheral Nerves Peripheral Nervous System Diseases Peripheral nerve injury Process Proliferating Protein Tyrosine Kinase Recovery Recovery of Function Regulation Schwann Cells Sensory Signal Transduction Specificity Techniques Testing Tetanus Helper Peptide Therapeutic Time Tissues Transgenic Mice Traumatic Nerve Injury Work axon growth axon regeneration base diabetic patient erbB-2 Receptor feeding high reward high risk in vivo imaging injured insight migration nerve injury painful neuropathy prevent repaired research study response spinal nerve posterior root

项目摘要

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.

描述（由适用提供）：外周神经损伤是常见的，每年在美国影响> 25万人。即使在手术修复后，完全恢复也很少。 > 90％的患者长期运动和感觉缺陷。功能恢复很差，因为周围神经很少在长距离上再生。长距离再生很大程度上失败了，因为Schwann细胞在受伤后会随着时间的流逝而失去支持轴突再生的能力。目前尚无治疗来鼓励雪旺细胞继续促进再生，甚至还不知道是否可以预防或逆转施旺恩细胞萎缩。我们最近发现，诱导的组成性活性ERBB2受体酪氨酸激酶（CAERBB2）的表达显着增强了Schwann细胞的再生促进能力。此外，我们的初步结果表明，CAERBB2使长期剥夺，贪食的Schwann细胞可以扩大，分裂，迁移和扩展过程。值得注意的是，我们观察到对免疫损伤的神经支配的雪旺细胞的影响很少，这表明治疗性的Caerbb2几乎没有靶向作用。在此R21应用中，我们建议进一步探索Caerbb2逆转Schwann细胞萎缩的可能性，并确定它是否促进了长距离轴突再生。 They 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 atrophited Schwann cells in chronically denervated nerve, and (2) if the Schwann cells reactivated by caErbB2 promote axon regeneration.这些概念证明实验将提供关键数据，以证明更大的赠款应用程序将调查CAERBB2引起的信号Cacades，确定其关键效果，定义CAERBB2有效性的治疗窗口，并开发出一种治疗上适用的方法来增强ERBB2信号。因此，拟议的工作有潜力为开发潜在治疗的强大基础，以使患者的长距离神经再生。