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.

哮喘在英国影响超过500万人，每年造成70,000次住院和13,000人死亡。尽管有许多治疗，许多患者仍然会出现重大症状。慢性哮喘的患者可以发展出称为气道重塑的结构性气道变化，从而增加症状的频率和严重程度。目前的哮喘疗法并不是迫切需要使用新的哮喘治疗方法来重塑气道的重塑。细胞外基质蛋白围绕所有提供支持但也会影响细胞功能的细胞。在重塑中，过量的细胞外基质蛋白胶原蛋白1和tenascin-c沉积在气道中。我们已经表明，这些蛋白质会导致称为MMP的酶的表达增加。我们认为，响应于胶原蛋白1和Tenascin-C的信号导致气道收缩和哮喘症状的信号响应的信号，MMP-1是由气道中的平滑肌细胞制成的。在这项研究中，我们将研究胶原蛋白1和Tenascin-C如何作用于平滑肌细胞以产生更多的MMP-1。接下来，我们将确定这些细胞外基质蛋白和MMP-1如何在哮喘实验模型中导致气道收缩增加。然后，我们将在人类哮喘中确认我们的发现：我们将使用没有肺部疾病的患者的样本，并将其与哮喘患者进行比较，并且响应标准的哮喘触发因素，气道温和，更强的气道变窄。通过研究这些患者肺中MMP-1，胶原蛋白I和Tenascin-C的表达，如果他们的气道更狭窄且哮喘症状更严重。我们希望这项研究将为药物提供潜在的新目标，以治疗气道重塑，减轻哮喘症状并改善患有哮喘患者的生活质量。