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

神经调节蛋白-1信号传导在调节脊髓损伤后修复和功能恢复中的作用

基本信息

批准号：
MR/P012418/1
负责人：
Elizabeth Bradbury
金额：
$ 74.06万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FP012418%2F1
关键词：
role neuregulin signalling modulating repair

项目摘要

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.

脊髓损伤（SCI）可能随时发生在任何人身上，瞬间改变生活，导致基本身体功能的严重和永久性丧失以及终生残疾。 SCI 的社会和经济影响是巨大的，而且还在不断增加，因为英国目前有 40,000 人患有 SCI，每年还有 1200 人受伤，而且医疗费用是所有医疗状况中最高的。目前尚无针对 SCI 患者的再生或疾病缓解疗法，目前的治疗主要集中于康复、症状缓解和支持治疗。因此，SCI 为医学研究提出了一个未满足的重大需求和高度优先事项。尽管 SCI 会造成严重的神经系统后果，但几乎所有病例在最初的创伤后都会出现一定程度的功能改善，并且在细胞水平上，脊髓会尝试进行再生反应，其中包括神经纤维发芽，髓磷脂修复和神经发生。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背后的基本生物学原理，我们也许能够调节和增强它们，并改善 SCI 后的功能结果。我们实验室的最新工作发现，一种重要的发育因子，称为神经调节蛋白-1 (Nrg1)，在创伤性 SCI 后自发髓磷脂修复和肢体功能恢复中发挥关键作用。缺乏Nrg1基因的小鼠患有严重的脱髓鞘病变，脊髓神经纤维的传导受损，并且在许多需要感觉运动协调和运动功能的任务中表现较差。我们现在希望了解控制这些过程的分子机制，并研究调节和增强 Nrg1 信号传导的潜力，以改善 SCI 后的功能结果。我们的初步数据表明，Nrg1 信号传导充当分子开关，使脊髓内的干细胞能够转化为修复性髓鞘细胞，并且 Nrg1 的不同亚型对于 SCI 后自发修复和功能的不同方面都很重要。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 Nrg1 的特定亚型是否可以改善和加速髓磷脂修复，恢复神经传导并调节肌肉和脊髓之间的感觉反馈，所有这些这是 SCI 后功能恢复的重要过程。这项研究不仅有利于我们对受损脊髓的生物学和介导功能修复的分子信号的基本了解，而且可能最终导致新的靶向再生疗法，以改善脊髓损伤SCI 后的功能结果。如果我们能够改善髓磷脂修复和沿着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，例如增强手指的抓力和感觉。恢复手和手指功能是四肢瘫痪患者的首要任务，因为这将使他们能够执行我们认为理所当然的日常任务（例如喂食、穿衣、洗澡），从而增强独立性并提高生活质量。因此，从长远来看，我们希望这项工作的最终受益者是脊柱损伤患者。然而，这项工作不仅与 SCI 相关，而且对其他中枢神经系统疾病也有更广泛的影响，例如多发性硬化症，改善髓磷脂修复和再生过程是其中的首要目标。