Recovery of normal breathing after chronic paralysis

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More than 2.5 million people worldwide live with the paralysis caused by spinal cord injury (SCI). When injuries such as spinal damage occur, the nerve cells at the point of the trauma die and a scar forms, which closes off the area and protects surrounding tissue. However, the scar also acts as a barrier to the regrowth of nerve fibres, thus the brain can no longer send signals to (or receive signals from) parts of the body. This results in partial or complete paralysis of the patient, for which there is currently no cure. One of the most common problems following SCI is partial or complete paralysis of the muscles required to breath. Indeed, failure or damage to respiratory (breathing) function is the main cause of death among people paralysed by SCI. Furthermore, patients have a hugely compromised quality of life due to reliance on artificial ventilation. Most research is focused on restoring respiratory function immediately following a SCI (acute). This research undoubtedly has benefits. However, most SCI patients are living with injuries long after the initial trauma (chronic). It is generally considered harder to recover function at chronic stages after an injury. However, there has been relatively little study into restoring the breathing of SCI patients at chronic stages of injury due to the extent of damage which has continued to occur over time. This is the focus of our study. Importantly, we aim to recovery normal breathing function long after the injury has occurred using methods which could be readily applied to human patients. Further, we want to understand the mechanism of this recovery of breath at chronic stages after trauma, which could help the development and optimisation of treatment strategies for chronic SCI patients. The diaphragm is the major muscle we use to breath. The circuity controlling its activity lies high up in the spinal cord (cervical), one of the most common place in SCI. Surrounding the circuity in a series of proteins, sugars and molecules which help the respiratory circuits function normally by stabilising it in a matrix. Previously, we have shown that breaking down this matrix can recover breathing up to 1.5 years after the initial trauma. But this treatment used a bacterial enzyme which cannot be given to humans. In this project, we want to test two new potential treatments which could be applied in the clinic to see if they have the same (or potentially better) effects to recover normal breathing. This will also determine how the matrix surrounding the respiratory cells prevents functional recovery following trauma. We shall look at how the respiratory pathways have reconnected following treatment, this will enable us to determine how best to help recovering function in the respiratory system following chronic trauma. In addition, we shall determine how respiratory muscle are affected by the long-term paralysis of chronic SCI and the extent to which they can regain function following recovery. Using these data, we will start to develop a tool that could help assessing injury level and direct treatment strategy for patients immediately after spinal trauma. Finally, we shall assess the changes which occur naturally in the respiratory system from acute to chronic time points following cervical SCI. This will demonstrate the degree to which the pathways that control breathing are trying (but not able) to regenerate naturally and where they are doing this. Further, we shall assess the matrix surrounding the circuity to determine the extent to which it is limiting this spontaneous recovery of breathing. This data will help optimising our clinically relevant treatment of chronic cervical SCI. In finding the mechanism of a clinically relevant treatment strategy to achieve functional respiratory recovery following chronic SCI, this research could signpost a way to one day alleviate the suffering of spinal cord injured people whom depend on artificial ventilation to survive.