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

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.

Spinal cord injury (SCI) results in profound and often lifelong disability, and there are no regenerative therapies. Despite the severe pathological and neurological deficits associated with SCI, some degree of spontaneous functional recovery is normally observed. Better understanding of underlying endogenous regenerative mechanisms could provide novel treatment avenues. We recently found that Neuregulin-1 (Nrg1), a growth factor which exists in multiple distinct isoforms, contributes to functional recovery following SCI. In this proposal we aim to understand the mechanisms by which Nrg1 signalling mediates spontaneous repair, remyelination and recovery after SCI and investigate whether targeted over expression of specific Nrg1 isoforms can improve functional outcome. Our previous and preliminary data suggest that Nrg1 signalling controls the differentiation of centrally derived glial progenitor cells into functional remyelinating cells after SCI. We will use transgenic technology to ablate Nrg1 receptors specifically in central glial progenitors and will determine the glial cell types (oligodendrocytes vs Schwann cells) regulated by Nrg-1 signalling and their functional importance, in mice with clinically relevant SCI (Aim 1). We also have evidence that specific Nrg1 isoforms mediate different aspects of endogenous repair after SCI. We will use viral vector-mediated axonal expression to determine whether manipulating Nrg1 isoforms can accelerate and enhance remyelination, resolve pathophysiology and improve functional outcome after SCI (Aim 2). Finally, secreted isoforms of Nrg1 are important in muscle spindle function and maintenance, which is important for optimum recovery following SCI. We will use isoform specific ablation to investigate whether muscle spindle-spinal cord communication is Nrg1-dependent (Aim 3). This work may lead to novel target-specific therapies for enhancing repair and improving functional outcome after SCI and other CNS disorders.

1. Who will benefit from this research?

The main beneficiaries of this research will be:
(i) The spinal cord injury (SCI) community; this includes SCI patients, their families, carers, supporters, charitable foundations, donors and SCI advocacy groups.
(ii) Scientists, clinicians, neurosurgeons, patients, carers and therapists who are interested in understanding the basic biology of the injured spinal cord and in research which may lead to future regenerative therapies for SCI.
(iii) Industry and academic partners as well as clinicians, who are interested in forming networks and consortia for dissemination of findings relating to potential regenerative therapies for SCI.
(iv) Wider groups of researchers interested in maximizing endogenous repair and improving functional outcome after many different types of CNS trauma as well as many disorders of the CNS (in particular disorders with a demyelinating pathology such as multiple sclerosis).
Thus, the wider field of regenerative medicine will benefit from new knowledge, new targets and potentially new therapies for improving myelin repair, tissue pathology and functional outcome in the injured or diseased CNS.

2. How will they benefit from this research?

This research will benefit the many stakeholders with an interest in regenerative research for SCI (including academic researchers, SCI patients and their families, carers, supporters, charitable foundations, donors, SCI advocacy groups, clinicians, neurosurgeons, therapists, industry and the government) by revealing new targets and regenerative therapies for improving functional outcome after SCI. Since there are currently no disease-modifying or regenerative therapies for SCI, finding molecular cues that lead to myelin repair and improved axonal conduction and functional outcome after SCI could have a huge social and economic impact. Restoring even small degree of function to a SCI patient (for example improved finger dexterity and sensation) could have a significant impact and lead to greater independence of SCI patients and improved quality of life for patients, their families and carers. As well as benefits to quality of life and health this would also have a significant economic impact, since the costs of SCI are among the highest of any medical condition and small improvements in function and ability could significantly reduce the economic costs of high dependence care. Thus, developing regenerative therapies for SCI is a top priority for medical research and if this project is successful it has the potential to significantly impact health, quality of life and economics. Therefore, it directly addresses one of the MRCs key Research Priority Themes: "Repair and replacement", whose objective is to translate the burgeoning knowledge in regenerative medicine into new treatment strategies.