Recovery of normal breathing after chronic paralysis

全世界有超过250万人患有脊髓损伤（SCI）引起的瘫痪。当发生脊髓损伤等损伤时，创伤点的神经细胞死亡，形成疤痕，从而封闭该区域并保护周围组织。然而，疤痕也是神经纤维再生的障碍，因此大脑不再能向身体的某些部位发送信号（或从身体的某些部位接收信号）。这导致患者部分或完全瘫痪，目前还没有治愈方法。SCI后最常见的问题之一是呼吸所需的肌肉部分或完全瘫痪。事实上，呼吸功能的衰竭或损伤是SCI瘫痪患者死亡的主要原因。此外，由于依赖人工通气，患者的生活质量大大降低。大多数研究都集中在SCI（急性）后立即恢复呼吸功能。这项研究无疑有好处。然而，大多数SCI患者在最初的创伤（慢性）之后很长时间都生活在损伤中。通常认为在损伤后的慢性阶段恢复功能更难。然而，由于损伤的程度随着时间的推移而持续发生，因此恢复SCI患者在慢性损伤阶段的呼吸的研究相对较少。这是我们研究的重点。重要的是，我们的目标是使用可以容易地应用于人类患者的方法在损伤发生后很长时间内恢复正常的呼吸功能。此外，我们希望了解创伤后慢性阶段呼吸恢复的机制，这可能有助于制定和优化慢性SCI患者的治疗策略。横隔膜是我们用来呼吸的主要肌肉。控制其活动的回路位于脊髓（颈部）的高处，这是SCI最常见的部位之一。在一系列蛋白质、糖和分子的包围下，呼吸回路通过稳定在基质中来帮助呼吸回路正常运作。以前，我们已经证明，打破这个矩阵可以恢复呼吸长达1.5年后，最初的创伤。但这种治疗方法使用了一种细菌酶，而这种酶不能用于人类。在这个项目中，我们想测试两种新的潜在治疗方法，它们可以应用于临床，看看它们是否具有相同（或可能更好）的效果来恢复正常呼吸。这也将决定呼吸细胞周围的基质如何阻止创伤后的功能恢复。我们将研究治疗后呼吸道是如何重新连接的，这将使我们能够确定如何最好地帮助慢性创伤后呼吸系统恢复功能。此外，我们将确定呼吸肌如何受到慢性SCI长期瘫痪的影响，以及恢复后它们可以恢复功能的程度。利用这些数据，我们将开始开发一种工具，可以帮助评估损伤水平和直接治疗策略的患者后，立即脊柱创伤。最后，我们将评估从急性到慢性的时间点在颈部脊髓损伤后呼吸系统自然发生的变化。这将证明控制呼吸的途径试图（但不能）自然再生的程度，以及它们在哪里这样做。此外，我们将评估回路周围的基质，以确定其限制呼吸自发恢复的程度。这些数据将有助于优化我们对慢性颈脊髓损伤的临床相关治疗。在寻找慢性SCI后实现功能性呼吸恢复的临床相关治疗策略的机制时，这项研究可以为有一天减轻脊髓损伤患者的痛苦指明方向，这些患者依赖人工通气生存。

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.