Extra-cellular matrix inducible collagenase activity in asthma: a potential drug target against airway remodelling.

哮喘中细胞外基质诱导的胶原酶活性：对抗气道重塑的潜在药物靶点。

• 批准号: G1100163/1
• 负责人: Simon Johnson
• 金额: $ 44.36万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1100163%2F1
• 关键词: Extra; cellular; matrix; inducible; collagenase

Asthma effects more than 5 million people in the UK and is responsible for 70,000 hospital admissions and 13,000 deaths each year. Despite treatment many patients still experience significant symptoms. Patients with chronic asthma can develop structural airway changes called airway remodelling which increase the frequency and severity of their symptoms. Airway remodelling is not well counted by current asthma therapies and new approaches to treat remodelling are urgently required. Extracellular matrix proteins surround all cells providing support but also effecting cell function. In remodelling, excessive amounts of the extracellular matrix proteins collagen 1 and tenascin-C are deposited in the airways. We have shown that these proteins can cause increased expression of enzymes called MMPs. We think that MMP-1, made by smooth muscle cells in the airways in response to signals from collagen 1 and tenascin-C leads to increased airway contraction and asthma symptoms. In this study, we will examine how collagen 1 and tenascin-C act on smooth muscle cells to produce more MMP-1. Next, we will determine how these extracellular matrix proteins and MMP-1 lead to increased airway contraction in an experimental model of asthma. We will then confirm our findings in human asthma: we will use samples from people with no lung disease and compare them with patients with asthma, with mild and stronger airway narrowing in response to a standard asthma trigger. By studying the expression of MMP-1, collagen I and tenascin-C in the lungs of these patients and if they have more airway narrowing and worse asthma symptoms. We hope this study will provide potential new targets for drugs to treat airway remodelling, reduce asthma symptoms and improve quality of life for those with asthma.

在英国，哮喘影响着500多万人，每年造成70，000人住院和13，000人死亡。尽管有治疗，许多患者仍然会出现明显的症状。慢性哮喘患者会发生气道结构性改变，称为气道重塑，这会增加其症状的频率和严重程度。目前的哮喘治疗没有很好地考虑气道重塑，迫切需要新的方法来治疗重塑。细胞外基质蛋白围绕所有细胞提供支持，但也影响细胞功能。在重塑中，过量的细胞外基质蛋白胶原蛋白1和腱生蛋白-C沉积在气道中。我们已经证明，这些蛋白质可以导致称为MMPs的酶的表达增加。我们认为，由气道平滑肌细胞响应胶原蛋白1和生腱蛋白-C的信号产生的MMP-1导致气道收缩增加和哮喘症状。在这项研究中，我们将研究胶原蛋白1和腱生蛋白-C如何作用于平滑肌细胞产生更多的MMP-1。接下来，我们将确定这些细胞外基质蛋白和MMP-1如何导致哮喘实验模型中气道收缩增加。然后，我们将证实我们在人类哮喘中的发现：我们将使用来自没有肺部疾病的人的样本，并将其与哮喘患者进行比较，这些患者对标准哮喘触发的反应是轻度和更强的气道狭窄。通过研究MMP-1、I型胶原和腱生蛋白-C在这些患者肺组织中的表达，以及他们是否有更多的气道狭窄和更严重的哮喘症状。我们希望这项研究能为治疗气道重塑、减轻哮喘症状和改善哮喘患者生活质量的药物提供潜在的新靶点。