The role of neuregulin-1 signalling in modulating repair and functional recovery following spinal cord injury

脊髓损伤(SCI)可以在任何时候发生在任何人身上，瞬间改变生命，导致严重和永久性的基本身体功能丧失和终身残疾。脊髓损伤的社会和经济影响是巨大的，而且还在不断增加，因为目前英国有4万人患有脊髓损伤，每年还有1200人受伤，医疗费用是所有医疗条件中最高的之一。目前还没有针对脊髓损伤患者的再生或疾病修正疗法，目前的治疗主要集中在康复、症状缓解和支持性护理上。因此，SCI是一个重大的未得到满足的需求，也是医学研究的高度优先事项。尽管脊髓损伤具有严重的神经系统后果，但在几乎所有病例中，在最初的创伤后，几乎所有病例的功能都有一定程度的改善，在细胞水平上，脊髓试图启动再生反应，包括神经纤维发芽、髓鞘修复和神经再生。尽管这种修复是有限的，但脊髓显然具有内源性修复能力。如果我们能够了解这些再生过程的基本生物学基础，那么我们就可以在脊髓损伤后对其进行调节和增强，并改善功能结果。我们实验室最近的工作发现，一种重要的发育因子，称为神经调节蛋白-1(Nrg1)，在创伤脊髓损伤后的自发髓鞘修复和肢体功能恢复中发挥关键作用。缺乏Nrg1基因的小鼠出现了严重的脱髓鞘病理，脊髓神经纤维传导受损，在一些需要感觉运动协调和运动功能的任务中表现较差。我们现在希望了解支配这些过程的分子机制，并研究调节和增强Nrg1信号以改善脊髓损伤后功能转归的可能性。我们的初步数据表明，Nrg1信号作为一个分子开关，使驻留在脊髓内的干细胞转化为修复性髓鞘细胞，不同亚型的Nrg1对脊髓损伤后自发修复和功能的不同方面具有重要意义。我们的目标是确定Nrg1如何介导修复，哪些细胞对Nrg1信号有反应，以及增加特定的Nrg1亚型是否可以改善和加速髓鞘修复，恢复神经传导和调节肌肉与脊髓之间的感觉反馈，所有这些都是脊髓损伤后功能恢复的重要过程。本研究不仅有助于我们对脊髓损伤的生物学和介导功能修复的分子信号的基本了解，而且最终可能导致新的靶向再生治疗，以改善脊髓损伤后的功能结果。如果我们能够改善髓鞘修复和沿脊髓传导神经冲动的能力，并恢复肌肉与脊髓的沟通，这可能会对功能能力产生巨大影响，例如通过增强手指的握力和感觉。恢复手和手指的功能是四肢瘫痪患者的当务之急，因为这将使他们能够执行我们认为理所当然的日常任务(如喂食、穿衣、洗澡)，从而提高独立性和生活质量。因此，从长远来看，我们希望这项工作的最终受益者将是脊柱损伤的患者。然而，这项工作不仅与脊髓损伤有关，而且对其他中枢神经系统疾病也有更广泛的影响，如多发性硬化症，改善髓鞘修复和再生过程是最重要的目标。

A spinal cord injury (SCI) can happen to anyone at any time, changing lives in an instant and resulting in severe and permanent loss of basic bodily functions and a lifetime of disability. The social and economic impact of SCI is immense and ever increasing, since 40,000 people are currently living with SCI in the UK, 1200 more sustain an injury each year and healthcare costs are among the highest of any medical condition. There are currently no regenerative or disease-modifying therapies for SCI patients, with current treatments focused predominantly on rehabilitation, symptomatic relief and supportive care. SCI therefore poses a major unmet need and a high priority for medical research. Despite the severe neurological consequences of SCI, in nearly all cases there is some degree of functional improvement after the initial trauma and, at the cellular level, there is some attempt by the spinal cord to mount a regenerative response, which includes nerve fibre sprouting, myelin repair and neurogenesis. Although this repair is limited, there is clearly an endogenous capacity for repair in the spinal cord. If we can understand the basic biology underlying these regenerative processes, we may then be able to modulate and enhance them and improve functional outcome after SCI.Recent work from our labs discovered that an important developmental factor, known as neuregulin-1 (Nrg1), plays a key role in spontaneous myelin repair and recovery of limb function after traumatic SCI. Mice that lacked the Nrg1 gene had a severe demyelinating pathology, impaired conduction of spinal nerve fibres and poorer performance in a number of tasks requiring sensorimotor coordination and locomotor function. We now wish to understand the molecular mechanisms that govern these processes and investigate the potential for modulating and enhancing Nrg1 signalling in order to improve functional outcome after SCI. Our preliminary data suggests that Nrg1 signalling acts as a molecular switch that enables stem cells resident within the spinal cord to transform into reparative myelinating cells, and that different sub-types of Nrg1 are important for different aspects of spontaneous repair and function after SCI. We aim to determine how Nrg1 mediates repair, what cells are responsive to Nrg1 signalling, and whether increasing specific sub-types of Nrg1 can improve and accelerate myelin repair, restore nerve conduction and modulate sensory feedback between the muscles and the spinal cord, all of which are processes important for recovery of function after SCI.This research will not only benefit our basic understanding of the biology of the injured spinal cord and the molecular signals that mediate functional repair but may ultimately lead to new targeted regenerative therapies for improving functional outcome after SCI. If we can improve myelin repair and the ability to conduct nerve impulses along the spinal cord, and restore muscle-spinal cord communication, this could have a huge impact on functional ability, for example by enhancing grip and sensation in the fingers. Regaining hand and finger function is a top priority for tetraplegic patients since it would enable them to perform daily tasks that we take for granted (such as feeding, dressing, washing), giving increased independence and improved quality of life. Thus, in the long term we hope that the ultimate beneficiaries of this work will be spinal injured patients. However, this work not only has relevance to SCI but also has wider implications for other central nervous system disorders, such as multiple sclerosis, where improving myelin repair and regenerative processes is a paramount goal.