A novel vascular approach to recovery of locomotor function after nerve injury

Recovery of function after injury to the nervous system is one of the most difficult challenges in medical sciences, and a combination of interventions is required to promote full recovery of function. We will investigate the benefits of microvascular & molecular therapy to support neurophysiological mechanisms recently shown to promote neural regeneration and behavioural improvements.

Traditional investigative pathways have provided beneficial treatments but the complex nature of neurodegeneration associated with age, trauma and disease requires an additional avenue. We will use an array of surgical, behavioural, histological, physiological and molecular techniques to investigate underlying mechanisms in a rodent model of spinal cord injury leading to partial restoration of mobility, in a project with potentially wide applications and impact.

We aim to:
1. Determine the benefits of enhanced microvascular recovery by angiogenic stimulation in an animal model of SCI (severe contusion injury). Recovery of motor and sensory function will be assessed following angiotherapy and in combination with locomotor training.
2. Determine whether improved neural blood flow and/or vascular remodelling may be manipulated to optimise therapy to enhance recovery of muscle function following peripheral neuropathy.

The novelty of our approach is recognising that the microcirculation is essential in tissue repair, e.g. tissue grafts and organ transplantation, but there is a dearth of information for its role in neural degeneration or repair. We have pilot data showing a) a drug successfully applied in muscle remodelling is also effective in increasing perineural blood flow; b) interventions that modify extracellular matrix around the spinal cord potentially enhance capillary growth. The combination of cell/molecular and physiological/behavioural interventions are clearly necessary to overcome the extensive challenges represented by SCI; this collaboration is unique in the UK in being able to combine such complex interventions in a rodent model of neural remodelling.

Neural degeneration and diminished plasticity is a common aspect of both healthy and pathological ageing. With conditions such as stroke, head trauma commonly affecting the elderly and the increasing age of the first incidence of spinal cord injuries, it is timely to understand the processes limiting recovery after such conditions. Additional relevance of this research includes the very high cost of healthcare associated with neurodegeneration or trauma, which represents a sustained burden. For example, care following spinal cord injuries is needed across the lifespan. Improving independence and quality of life will have profound benefits for the individual, and significantly reduce healthcare burden. The median age of incidence of SCIs has shifted from the 20's to 50-60's, with a sharp increase for the older than 70yo in the last 20 years (McCaughley et al Spinal Cord 2016).

While there are currently no approved interventions that lead to complete recovery of function after SCI but it is timely to improve therapeutic strategies, given recent discoveries that promote partial recovery of locomotor function. Rehabilitation is currently the only effective intervention with positive effects on functional recovery. Applying an adjunct therapy based on understanding of cellular mechanisms is a potentially powerful new avenue for improving clinical outcome.