Recovery of normal breathing after chronic paralysis

慢性瘫痪后恢复正常呼吸

• 批准号: MR/S011110/1
• 负责人: Jessica Chi Fung Kwok
• 金额: $ 81.61万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS011110%2F1
• 关键词: Recovery; normal; breathing; after; chronic

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.

全球有超过 250 万人因脊髓损伤 (SCI) 导致瘫痪。当发生脊髓损伤等损伤时，受伤处的神经细胞会死亡并形成疤痕，从而封闭该区域并保护周围组织。然而，疤痕也成为神经纤维再生的障碍，因此大脑无法再向身体部位发送信号（或从身体部位接收信号）。这会导致患者部分或完全瘫痪，目前尚无治愈方法。脊髓损伤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，呼吸功能衰竭或受损是 SCI 瘫痪患者死亡的主要原因。此外，由于依赖人工通气，患者的生活质量受到严重影响。大多数研究的重点是在 SCI（急性）后立即恢复呼吸功能。这项研究无疑是有好处的。然而，大多数 SCI 患者在初次创伤（慢性）后很长一段时间仍带着伤害生活。人们普遍认为，在受伤后的慢性阶段恢复功能比较困难。然而，由于损伤程度随着时间的推移而持续发生，因此关于恢复处于慢性损伤阶段的 SCI 患者的呼吸的研究相对较少。这是我们研究的重点。重要的是，我们的目标是使用易于应用于人类患者的方法，在受伤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，这有助于慢性SCI患者治疗策略的制定和优化。横膈膜是我们用来呼吸的主要肌肉。控制其活动的电路位于脊髓（颈部）的高处，这是脊髓损伤中最常见的部位之一。呼吸回路周围有一系列蛋白质、糖和分子，通过将其稳定在基质中来帮助呼吸回路正常运作。之前，我们已经证明，打破这个矩阵可以在初次创伤后 1.5 年内恢复呼吸。但这种治疗使用了一种不能用于人类的细菌酶。在这个项目中，我们想要测试两种可应用于临床的新的潜在治疗方法，看看它们是否具有相同（或可能更好）的恢复正常呼吸的效果。这也将决定呼吸细胞周围的基质如何防止创伤后的功能恢复。我们将研究治疗后呼吸通路如何重新连接，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功能的恢复。此外，我们还应确定慢性 SCI 的长期麻痹对呼吸肌的影响以及恢复后其功能恢复的程度。利用这些数据，我们将开始开发一种工具，可以帮助评估脊柱创伤后患者的损伤程度并立即指导治疗策略。最后，我们将评估颈椎 SCI 后从急性到慢性时间点自然发生的呼吸系统变化。这将证明控制呼吸的通路尝试（但不能）自然再生的程度以及它们在哪里进行再生。此外，我们将评估回路周围的矩阵，以确定其限制呼吸自主恢复的程度。这些数据将有助于优化我们对慢性颈椎 SCI 的临床相关治疗。在寻找临床相关治疗策略的机制以实现慢性 SCI 后功能性呼吸恢复的过程中，这项研究可能为有一天减轻依赖人工通气生存的脊髓损伤患者的痛苦指明了方向。

项目成果

Peripherally delivered Adeno-associated viral vectors for spinal cord injury repair

• DOI: 10.1016/j.expneurol.2021.113945
• 发表时间: 2021-12
• 期刊: Experimental Neurology
• 影响因子: 5.3
• 作者: Jared D Sydney-Smith;A. B. Spejo;P. Warren;L. Moon

New Model of Ventral Spinal Cord Lesion Induced by Balloon Compression in Rats.

• DOI: 10.3390/biomedicines8110477
• 发表时间: 2020-11-05
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Krupa P;Stepankova K;Kwok JC;Fawcett JW;Cimermanova V;Jendelova P;Machova Urdzikova L
• 通讯作者: Machova Urdzikova L

Muscling in on neurorehabilitative strategies to counter respiratory motor dysfunction in cervical spinal cord injury.

加强神经康复策略以应对颈脊髓损伤中的呼吸运动功能障碍。

• DOI: 10.1113/jp281042
• 发表时间: 2021
• 期刊: The Journal of physiology
• 作者: O'Halloran KD

Oral treatment of 4-methylumbelliferone reduced perineuronal nets and improved recognition memory in mice.

• DOI: 10.1016/j.brainresbull.2022.01.011
• 发表时间: 2022-04
• 期刊: Brain research bulletin
• 影响因子: 3.8
• 作者: Dubisova J;Burianova JS;Svobodova L;Makovicky P;Martinez-Varea N;Cimpean A;Fawcett JW;Kwok JCF;Kubinova S
• 通讯作者: Kubinova S

New insights into glial scar formation after spinal cord injury.

• DOI: 10.1007/s00441-021-03477-w
• 发表时间: 2022-03
• 期刊: Cell and tissue research
• 影响因子: 3.6
• 作者: Tran AP;Warren PM;Silver J
• 通讯作者: Silver J