A novel approach to improve the repair of injured peripheral nerves

改善受损周围神经修复的新方法

• 批准号: MR/R023816/1
• 负责人: Alison Lloyd
• 金额: $ 37.82万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR023816%2F1
• 关键词: novel; approach; improve; repair; injured

Peripheral nerves connect our tissues and organs to the Central Nervous System (CNS) and are important for movement, our senses and much of the unconscious control of many of our organs. Unlike, the CNS, the Peripheral Nervous System (PNS) is capable of regeneration following injury. This is why movement can be re-established in a reconnected amputated limb, whereas injuries affecting the CNS, such as spinal damage are much less likely to repair. Despite the intrinsic ability of peripheral nerves to repair, the process is not perfect. Following severe injuries, grafts are needed to bridge the region of damage but these have limitations and there is a huge impetus to develop improved artificial grafts. Moreover, following even minor nerve damage, aberrant regeneration can occur which often fails to resolve and can result in the development of pain. Understanding the physiological mechanisms by which peripheral nerves can regenerate following injury should enable improvements in the treatment of severe nerve injuries, provide strategies for the treatment of neuropathic pain and perhaps provide insight into how to improve repair of the CNS.Following the breakage of a nerve, the nerve cells degenerate downstream of the injury separating the nerve cells from their target tissues. The regeneration process therefore requires the regrowth of the nerve cells back to their targets. We have shown that at the site of injury this process is enabled by another cell type, Schwann cells, which are the major glial cell type of the PNS. These cells migrate as cords across the injury site and take the regrowing nerve cells along with them on their surface. Inflammatory cells accumulate at the injury site and we have discovered that these cells secrete a factor that stimulates Schwann cell migration. The identification of this previously unknown Schwann cell chemotactic factor has important implications as it may be beneficial in stimulating Schwann cell migration and hence nerve cell regrowth in artificial grafts. Moreover, inhibition of this factor may attenuate the aberrant nerve regeneration associated with pain. The aim of this proposal is to test, using in vivo models, whether the identification of a potent Schwann cell chemotactic factor will result in therapeutic benefits. To test this we will do the following:1. Test the ability of this factor to improve nerve regeneration in artificial grafts.2. Test the effects of inhibiting the chemotactic factor to determine its potential as a therapeutic target for the treatment of aberrant regeneration.3. To characterise the inflammatory cells responsible for the secretion of the Schwann cell chemotactic factor.The completion of this study should determine the therapeutic potential of using this Schwann cell chemotactic factor to improve nerve repair and/or as a novel drug target to resolve the aberrant nerve regeneration associated with pain. If successful, partners will be sought to take these findings towards the clinic.

外周神经将我们的组织和器官与中枢神经系统（CNS）连接起来，对我们的运动、感觉和许多器官的无意识控制都很重要。与中枢神经系统不同，周围神经系统（PNS）在损伤后能够再生。这就是为什么在重新连接的截肢肢中可以重新建立运动，而影响中枢神经系统的损伤，如脊柱损伤，则不太可能修复。尽管周围神经具有内在的修复能力，但修复过程并不完美。在严重损伤后，需要移植物来桥接损伤区域，但这些都有局限性，并且有巨大的动力来开发改进的人工移植物。此外，即使是轻微的神经损伤，也可能发生异常再生，这往往无法解决，并可能导致疼痛的发展。了解损伤后周围神经再生的生理机制将有助于改善严重神经损伤的治疗，为神经性疼痛的治疗提供策略，并可能为如何改善中枢神经系统的修复提供见解。随着神经断裂，神经细胞向损伤的下游退化，使神经细胞与目标组织分离。因此，再生过程需要神经细胞重新生长回到它们的目标。我们已经证明，在损伤部位，这一过程是由另一种细胞类型雪旺细胞激活的，雪旺细胞是PNS的主要胶质细胞类型。这些细胞像绳索一样在损伤部位移动，并将再生的神经细胞带到它们的表面。炎症细胞在损伤部位聚集，我们发现这些细胞分泌一种刺激雪旺细胞迁移的因子。这种以前未知的雪旺细胞趋化因子的鉴定具有重要意义，因为它可能有利于刺激雪旺细胞的迁移，从而促进人工移植物中神经细胞的再生。此外，抑制该因子可能会减弱与疼痛相关的异常神经再生。本提案的目的是测试，使用体内模型，是否鉴定一种有效的雪旺细胞趋化因子将导致治疗效益。为了测试这一点，我们将做以下操作：试验该因子促进人工移植物神经再生的能力。测试抑制趋化因子的作用，以确定其作为治疗异常再生的治疗靶点的潜力。表征负责分泌雪旺细胞趋化因子的炎症细胞。这项研究的完成将确定使用这种雪旺细胞趋化因子来改善神经修复和/或作为一种新的药物靶点来解决与疼痛相关的异常神经再生的治疗潜力。如果成功，将寻求合作伙伴将这些发现用于临床。

项目成果

The regulation of the homeostasis and regeneration of peripheral nerve is distinct from the CNS and independent of a stem cell population.

周围神经的稳态和再生的调节不同于中枢神经系统并且独立于干细胞群。

• DOI: 10.1242/dev.170316
• 发表时间: 2018-12-14
• 期刊: Development (Cambridge, England)
• 作者: Stierli S;Napoli I;White IJ;Cattin AL;Monteza Cabrejos A;Garcia Calavia N;Malong L;Ribeiro S;Nihouarn J;Williams R;Young KM;Richardson WD;Lloyd AC
• 通讯作者: Lloyd AC

HDAC3 Regulates the Transition to the Homeostatic Myelinating Schwann Cell State.

HDAC3 调节向稳态髓鞘雪旺细胞状态的转变。

• DOI: 10.1016/j.celrep.2018.11.045
• 发表时间: 2018
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Rosenberg LH

Macrophages Enforce the Blood Nerve Barrier

巨噬细胞强化血神经屏障

• DOI: 10.1101/493494
• 发表时间: 2019
• 作者: Malong L