Recovery of normal breathing after chronic paralysis

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.

Respiratory failure is the leading cause of morbidity and mortality following acute and chronic spinal cord injury (SCI). This is largely due to diaphragm paralysis resulting from damage to descending bulbospinal projections. The human respiratory motor system shows no endogenous recovery from SCI acutely or chronically after injury. Nonetheless, we have shown that total recovery of respiratory motor function is possible 1.5 years following cervical SCI following modification of the extracellular matrix (ECM) at the phrenic motor pool. However, this was achieved using methods that could not be readily applied to human patients. Here, we aim to assess two clinically applicable methods of ECM modification to determine if total and persistent recovery of normal respiratory motor function can be achieved at chronic stages following SCI. Through the use of these drugs, we shall be also able to determine if restoration of respiratory function is reliant on regeneration or plasticity while assessing the anatomical and physiological mechanism for this recovery: the degree to which it relies upon endogenous plasticity, the motor circuity involved, and the function and mechanism of the ECM involvement. Further, we shall assess the degree to which paralysed diaphragm muscle losses, and can regain, mechanical function following SCI and treatment and start development of a tool which will utilise respiratory parameters to assess the severity of SCI and predict treatment outcomes. Finally, we shall explore and identify the endogenous alterations to the respiratory motor system which occur over time following trauma. These data will inform the optimal time for treatment application post SCI. Collectively, this project will demonstrate the mechanism of functional recovery within the respiratory motor system as a whole following chronic and severe cervical trauma while allowing for greater translation of ideas and treatments for chronic SCI into the clinic.

Outside of academic beneficiaries, there are a number of groups and communities who will benefit from the impact of this work. Firstly, the UK science programme. No other researchers currently working in the UK assess respiratory motor dysfunction following trauma to the central nervous system. This project would secure these unique skills and knowledge within the UK and, in doing so, facilitate the development and enhancement of the countries research base. In addition, this project would strengthen UK/USA research collaboration and networking.

Secondly, the project will have an impact on the general public and school pupils. We shall work with the Communication and Media team at the University of Leeds to promote the research with press releases to coincide with publication. We shall communicate with the Universities outreach and engagement officers to identify appropriate opportunities to disseminate work to the public. This would include programmes such as the annual 'Discovery Zone' (aimed to encourage school aged pupils into science) or the yearly 'Be Curious' festival, aimed at engaging the public with scientific knowledge. The applicants will join the 'Women in Leeds' group to aid public engagement about females in science and give a platform to discuss the work performed. Appropriate level information will be placed on websites and regularly updated and the PI's will participate in awareness events such as charity runs. This dissemination of the project's ideas, objectives, and outcomes will help fostering public interest and support of the sciences, both critical factors in the persistence of public funded grant programs and the fostering of new scientists within young people.

The project is of additional benefit to spinal cord injury (SCI) patients or individuals with respiratory motor deficits. Over 50,000 people in the UK and Ireland live with the paralysis caused by SCI, with 3 new cases occurring every day. This project is pre-clinical in design, meaning that it will not have an immediate impact on clinical treatment. However, this study addresses key unmet areas of basic research which will have wide ranging implications for the SCI community including the assessment of treatments which can readily be taken for clinical trial (one of which already has clinical approval). Further, the data produced will help make a tool to predict outcome measure at the point of trauma, which would help in the design of stratify treatments at the clinical level. The data hold great promise for the better treatment of chronic respiratory dysfunction following SCI and the future development of treatment strategies for clinical patients. Due to the public dissemination of the project (discussed above), the community of patients will be educated in the recent scientific developments facilitating optimism for the future.

The project will impact pharmaceutical/biotech companies. As this work does not involve the assessment or creation of a patentable drug or tool, and is at a pre-clinical stage, it is will not provide pharmaceutical or biotech companies with a product to test and market. However, these data provide greater insight into: 1) how injuries change over time, and 2) how best to recover SCI at chronic stages. This can give valuable understanding of how best to run clinical trials, facilitating the development and translation of treatments into the clinic.