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

• 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

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.

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.

项目成果

Inhibiting an inhibitor: a decoy to recover dexterity after spinal cord injury.

抑制抑制剂：脊髓损伤后恢复灵活性的诱饵。

• DOI: 10.1093/brain/awaa175
• 发表时间: 2020
• 期刊: a journal of neurology
• 作者: Bradbury EJ