Interplay of the extracellular matrix and immune cells in lung pathology: key role for chitinase-like proteins

肺病理学中细胞外基质和免疫细胞的相互作用：几丁质酶样蛋白的关键作用

• 批准号: MR/Y003683/1
• 负责人: Tara Elaine Sutherland
• 金额: $ 89.51万
• 依托单位: University of Aberdeen
• 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=MR%2FY003683%2F1
• 关键词: Interplay; extracellular; matrix; immune; cells

BackgroundAsthma is a complex inflammatory disease, and as such research has focussed on understanding and treating airway inflammation. In some asthma sufferers, anti- inflammatory agents work well to control symptoms and exacerbations. However, these drugs don't always improve lung function and in severe asthma, some patients fail to see any improvement after anti-inflammatory treatments. The asthmatic airway also undergoes pathological changes that result in airway remodelling. Remodelling results in the extracellular matrix components (e.g. collagens) being deposited and reorganised within the lung architecture making the lungs stiff and rigid, ultimately reducing the ability of the lungs to function. Current research suggests remodelling may occur separately from inflammation, explaining why anti-inflammatories don't always improve lung function in asthma. We have shown that chitinase-like proteins (CLPs), molecules that are highly produced in the lungs of people with asthma, contribute to remodelling responses. The higher the concentration of CLPs, the more severe the asthma and remodelling. Using mouse models, we have shown that inhibiting CLPs can reverse asthma remodelling. However, we still need to understand how CLPs work and what causes remodelling to occur in the first place, in order to come up with new therapies that will successfully treat asthma and improve lung function.Questions we will ask during this project:1) How do CLPs, inflammatory cells and tissue structural cells communicate with each other to trigger remodelling? 2) What does inhibiting CLPs do to cells/molecules to breakdown the matrix and reverse remodelling?3) When remodelling occurs, does it change the way the lungs can respond to inflammatory challenges like allergens?How will we answer these questions?Some of the work will use a mouse model that involves giving mice a cocktail of allergens (dust mites, fungi, pollen) frequently encountered by people. Importantly, this mouse model shares common features with severe asthma in people and can be used to study disease pathways in ways that cannot be done in people. We will measure how the lung matrix changes after exposure to aero-allergens, focusing on the location of initial remodelling events and the inflammatory or tissue cells accumulate around these areas. As CLPs contribute to the initiation of remodelling, we will investigate whether interfering with CLPs changes the behaviour of cells important for initiating lung remodelling.Next, we will investigate how to reverse remodelling and hence improve lung function, asking questions about how CLPs breakdown the matrix. Using the mouse allergen model, in addition to isolated mouse and human lung cells, we will determine what pathways, cells and molecules that degrade the matrix are changed when CLPs are inhibited. This research will allow us to identify future targets for making drugs that can reverse remodelling in asthma.Lastly, we will investigate the consequences of lung remodelling during asthma. Inflammatory cells need to navigate their way through the matrix before entering the lung. If the matrix changes, like it does in asthma, it will alter the way cells get into the lung. Using mouse models, and cultures of human and mouse cells, we can manipulate cells/matrix to determine how asthma remodelling influences lung inflammation and ultimately the way the lungs can respond to allergens and molecules that trigger inflammatory responses. What do we hope to achieve overall?We will gain an understanding of how lung matrix proteins change in response to asthma triggers, like allergens, and whether these matrix changes dictate the type of airway inflammation a person has or the type of asthma that develops. Critically, we will determine ways in which remodelling can be reversed, and already have a unique lead to investigate this through manipulation of CLPs.

背景性是一种复杂的炎症性疾病，因此，此类研究的重点是理解和治疗气道炎症。在某些哮喘患者中，抗炎药可以很好地控制症状和恶化。但是，这些药物并不总是改善肺功能，并且在严重的哮喘中，有些患者在抗炎治疗后没有得到任何改善。哮喘气道还经历了导致气道重塑的病理变化。重塑导致细胞外基质成分（例如胶原蛋白）被沉积并重组在肺结构中，从而使肺部僵硬且刚性僵硬，最终降低了肺部功能的能力。当前的研究表明，重塑可能与炎症分开发生，这解释了为什么抗炎药并不能总是在哮喘中提高肺功能。我们已经表明，在哮喘患者的肺中高度生产的几丁质酶样蛋白（CLP）有助于重塑反应。 CLP的浓度越高，哮喘和重塑越严重。使用鼠标模型，我们表明抑制CLP可以逆转哮喘的重塑。但是，我们仍然需要了解CLP的工作原理以及最初发生重塑的原因，以提出新的疗法，这些疗法将成功治疗哮喘并改善肺功能。我们将在此项目中提出问题：1）CLP，炎症细胞和组织结构细胞如何相互传达以触发重塑？ 2）抑制CLP对细胞/分子的影响如何分解矩阵和反向重塑？3）当进行重塑时，它会改变肺部可以应对炎症挑战的方式，例如过敏原？我们将如何回答这些问题？我们将使用一些鼠标来涉及鼠标的鸡巴鸡尾酒（频繁地给粉尘）粉尘（Eltergementer），粉尘粉碎了粉尘，粉丝（endererge），粉丝（endererge），粉丝（enderergement），粉丝（enderergement），粉丝（enderergement），粉丝（endererge）。重要的是，该小鼠模型在人们的严重哮喘中具有共同的特征，可用于以人无法做到的方式研究疾病途径。我们将测量暴露于气动过敏原后的肺基质如何变化，重点是初始重塑事件的位置以及在这些区域周围积累的炎症或组织细胞。由于CLP有助于启动重塑，我们将调查是否会干扰CLPS是否会改变启动肺部重塑重要的细胞行为。次要，我们将研究如何逆转重塑并因此改善肺功能，从而提出有关CLPS损坏矩阵的问题。使用小鼠过敏原模型，除了分离的小鼠和人类肺细胞外，我们还将确定在抑制CLP时更改基质的途径，细胞和分子。这项研究将使我们能够确定生产可以在哮喘中逆转重塑的药物的未来靶标的。炎症细胞在进入肺之前需要通过基质导航。如果矩阵改变，就像在哮喘中一样，它将改变细胞进入肺的方式。使用小鼠模型以及人类和小鼠细胞的培养物，我们可以操纵细胞/基质，以确定哮喘重塑如何影响肺部炎症以及最终对肺部对触发炎症反应的过敏原和分子的反应方式。我们希望总体上实现什么？我们将了解肺部基质蛋白如何响应哮喘触发因素（例如过敏原）如何变化，以及这些基质变化是否决定了一个人具有的气道炎症类型或发生的哮喘类型。至关重要的是，我们将确定可以逆转重塑的方法，并且已经具有独特的引线来通过操纵CLP进行调查。