Bioactive fragments of the extracellular matrix orchestrate lung epithelial cell repair.

细胞外基质的生物活性片段协调肺上皮细胞修复。

• 批准号: BB/Y004183/1
• 负责人: Robert Snelgrove
• 金额: $ 82.8万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY004183%2F1
• 关键词: Bioactive; fragments; extracellular; matrix; orchestrate

On a daily basis, our lungs are exposed to an array of environmental insults including viruses, bacteria and toxic particles. Specialised 'epithelial' cells run from our nose all the way down to the depths of our lungs, forming a barrier to the external environment and protecting us from these insults. However, these epithelial cells are frequently and sometimes severely damaged by these exposures. It is critical that after injury, the epithelial cells are quickly repaired to restore this barrier. If epithelial cells are not efficiently repaired then we are more prone to infection, and our ability to breathe is compromised. The lungs are able to repair themselves when damaged but this ability deteriorates as we get older and in some people the repair process doesn't work properly, leading to disease. Currently, there are no treatments able to restore damaged lung tissue, and this is clearly an urgent clinical need. A greater understanding of how the lungs repair themselves is required to promote long term lung health and to identify new treatments that can promote lung repair. The extracellular matrix (ECM) is a three-dimensional meshwork of proteins and other factors that supports the structure of the lungs and acts as a scaffold for cells that populate the lungs. We are interested in a small fragment of this ECM called Pro-Gly-Pro (PGP), which is normally hidden but becomes released from the ECM in response to infection or injury. We have exciting data that demonstrates that PGP is potent at promoting repair responses in lung epithelial cells. Furthermore, PGP can also operate to drive the influx of cells called neutrophils into the lungs. Neutrophils are essentially the soldiers of our immune system that can kill any invading organisms that have entered the lung as a result of injury. Therefore, we believe that PGP is a fragment of the lung tissue that is released in response to injury and then subsequently acts to direct localised epithelial repair to seal the breach to the external environment, whilst simultaneously causing the influx of neutrophils to sterilise the lung tissue. We also believe that pathways governing the levels of PGP may be disrupted in disease settings. Consequently, understanding how PGP promotes repair responses could yield novel treatments to counteract lung injury. Because the ECM is a critical component of all tissues, our data is highly likely to also be relevant for repair of other organs in the body. In this proposal, we want to understand more about how PGP drives repair in epithelial cells and ascertain the relative importance of PGP as a mediator of repair following lung injury. We will use epithelial cells isolated from the lungs of healthy individuals to probe how exactly PGP is able to drive repair responses, thus revealing potential strategies for therapeutic intervention. Subsequently, we will induce micro-injuries in slices of human and mouse lung tissue that are essentially 'mini lungs' and assess how manipulation of PGP in this more complex 3D setting modulates subsequent repair responses. The use of human lung cells and tissue is critical if we are to understand the importance of PGP to human lung injury and repair. However, to truly demonstrate the capacity of PGP to instigate lung repair and minimize pathology over a prolonged period of time, it is also necessary to assess the role of PGP in a mouse model of lung epithelial cell injury. We will determine the importance of naturally generated PGP in supporting epithelial repair and also ascertain to what extent supplementation of PGP can enhance repair. The results of this proposal could lead in future to new treatments that can promote lung repair via modulation of PGP.

每天，我们的肺暴露于一系列环境侮辱，包括病毒，细菌和有毒颗粒。专门的“上皮”细胞一直从我们的鼻子一直延伸到我们的肺部深处，形成了外部环境的障碍，并保护了我们免受这些侮辱。但是，这些上皮细胞经常受到这些暴露的严重损害。至关重要的是，在受伤后，上皮细胞会迅速修复以恢复该障碍。如果上皮细胞没有有效地修复，那么我们更容易感染，并且我们的呼吸能力也会受到损害。肺部受损时能够修复自身，但是随着年龄的增长，这种能力会恶化，在某些人中，维修过程无法正常工作，导致疾病。当前，尚无治疗方法可以恢复受损的肺组织，这显然是紧急的临床需求。对肺部修复的方式有更深入的了解，以促进长期肺部健康并确定可以促进肺部修复的新疗法。细胞外基质（ECM）是蛋白质和其他因素的三维网状，该因子支持肺的结构，并充当占肺部填充的细胞的脚手架。我们对这个称为Pro-Gly-Pro（PGP）的ECM的小片段感兴趣，该片段通常被隐藏，但由于感染或损伤而从ECM中释放出来。我们有令人兴奋的数据，表明PGP在促进肺上皮细胞中的修复反应方面有效。此外，PGP还可以运行以将称为中性粒细胞的细胞涌入肺部。中性粒细胞本质上是我们免疫系统的士兵，可以杀死因受伤而进入肺部的任何入侵生物。因此，我们认为PGP是肺组织的碎片，它是响应损伤而释放的，然后作用于指导局部上皮修复，以将突破封闭到外部环境，同时导致中性粒细胞的流入以消毒肺组织。我们还认为，在疾病环境中，管理PGP水平的途径可能会破坏。因此，了解PGP如何促进修复反应可能会产生新的治疗方法以抵消肺损伤。由于ECM是所有组织的关键组成部分，因此我们的数据很可能与体内其他器官的修复有关。在此提案中，我们想更多地了解PGP如何驱动上皮细胞的修复，并确定PGP作为肺损伤后修复的介体的相对重要性。我们将使用从健康个体肺部分离的上皮细胞来探测PGP确切能够驱动修复反应的方式，从而揭示治疗干预的潜在策略。随后，我们将在人和小鼠肺组织的切片中诱导微型伤害，这些切片本质上是“微型肺”，并评估在这种更复杂的3D设置中对PGP的操纵如何调节后续的维修反应。如果我们要了解PGP对人肺损伤和修复的重要性，那么人类肺细胞和组织的使用至关重要。但是，为了真正证明PGP在长时间内促进肺修复和最小化病理的能力，还必须评估PGP在肺上皮细胞损伤的小鼠模型中的作用。我们将确定自然产生的PGP在支持上皮修复方面的重要性，并确定PGP的补充在多大程度上可以增强修复。该提案的结果可能会导致未来通过调节PGP促进肺修复的新治疗方法。