Promoting axon regeneration and functional recovery after SCI

促进 SCI 后轴突再生和功能恢复

• 批准号: 9334947
• 负责人: ZHIGANG HE
• 金额: $ 38.72万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334947
• 关键词: Address; Adult; Anatomy; Axon; Binding; Biological; Body part; Brain; Brain-Derived Neurotrophic Factor; Bypass; Cell Adhesion Molecules; Complement 5a; Corticospinal Tracts; Crush Injury; Dorsal; Electrophysiology (science); Extracellular Protein; FRAP1 gene; Failure; Forelimb; Growth; Growth Factor; IGF1 gene; Injury; Integrins; Lesion; Mediating; Methods; Modeling; Motor; Natural regeneration; Nature; Neurons; Optic Nerve Injuries; PTEN gene; Paralysed; Pathway interactions; Pilot Projects; Recovery of Function; Refractory; Regenerative response; Retinal Ganglion Cells; STAT3 gene; Safety; Signal Pathway; Site; Spinal; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Structure of rubrospinal tract; Testing; Therapeutic; Translating; Tumor Suppressor Proteins; axon injury; axon regeneration; base; clinical application; clinically relevant; combinatorial; functional outcomes; functional restoration; injured; juvenile animal; neurodevelopment; osteopontin; overexpression; receptor; regenerative; relating to nervous system; repaired; reticulospinal tract

PROJECT SUMMARY Spinal cord injury (SCI) results in the loss of voluntary control of the body part below the injury site. Severed connection between the brain neurons with long-projecting descending axons and the spinal circuits below the lesion is one main cause of such paralysis. Thus, promoting transected axons to regenerate across lesion represents the most ideal strategy for re-building circuits and restoring functions. However, these adult descending axons are regeneration-refractory. Recent studies suggested that a key reason for their regeneration failure is the diminished intrinsic regenerative capacity after injury in adult. In this regard, we and others showed that deletion of PTEN, a negative regulator of mTOR, in either young or adult corticospinal neurons is able to activates their intrinsic regenerative ability, resulting in robust re-growth of transected corticospinal tract (CST) axons. While providing new venues of enabling injured CST axons to mount a regenerative response, these results raise several challenges towards translating these findings to a possible therapeutic strategy. First, while PTEN deletion in cortical neurons resulted in significant CST regrowth, achieving robust and long-distance regeneration for functional recovery might need further optimization of the intrinsic regenerative ability of these mature corticospinal neurons. Second, considering the importance of other descending tracts (in addition to CST), it is important to assess whether their regenerations are also regulated by such manipulations. Third, While PTEN inhibition provides a valuable manipulation for proof-of- principle studies, the biological nature of PTEN as a tumor suppressor raises safety concerns for its clinical application. Thus, it is crucial to develop other safe methods of mimicking the effects of PTEN inhibition in activating mTOR and promoting axon regeneration and functional recovery. The proposed studies in this application will extend our recent exciting findings to address each of these issues, in a hope to develop clinically relevant neural repair strategies for spinal cord injury.

项目摘要 脊髓损伤（SCI）导致对受伤部位以下身体部位的自主控制丧失。切断 具有长投射下行轴突的脑神经元和脊髓回路之间的连接 病变是造成这种瘫痪主要原因之一。因此，促进横断的轴突穿过损伤再生， 代表了重建电路和恢复功能的最理想策略。然而，这些成年人 下行轴突是再生难治性的。最近的研究表明，一个关键的原因， 再生失败是指成年人损伤后内在再生能力下降。在这方面，我们和 其他研究表明，无论是年轻人还是成年人， 神经元能够激活其内在的再生能力，导致横断的神经元的稳健再生长。 皮质脊髓束（CST）轴突。同时提供新的场所，使受伤的CST轴突安装一个 再生反应，这些结果提出了一些挑战，将这些发现转化为可能的 治疗策略首先，虽然皮质神经元中的PTEN缺失导致显著的CST再生长， 实现功能恢复的强大和长距离再生可能需要进一步优化 这些成熟的皮质脊髓神经元的内在再生能力。第二，考虑到 其他下行道（除了CST），重要的是要评估它们的再生是否也 受这种操纵的影响。第三，虽然PTEN抑制提供了一个有价值的操纵证明， 原则研究，PTEN作为肿瘤抑制因子的生物学性质引起了其临床应用的安全性问题。 应用程序.因此，开发其他安全的方法来模拟PTEN抑制在肿瘤细胞中的作用是至关重要的。 激活mTOR，促进轴突再生和功能恢复。本研究中提出的研究 应用程序将扩展我们最近令人兴奋的发现，以解决这些问题中的每一个，希望开发 脊髓损伤的临床相关神经修复策略。