A Life Course Approach to Investigating Asthma Pathogenesis and Progression

研究哮喘发病机制和进展的生命全程方法

• 批准号: G0900453-E01/1
• 负责人: Stephen Holgate
• 金额: $ 275.04万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0900453-E01%2F1
• 关键词: Life; Course; Approach; Investigating; Asthma; Life; Course; Approach; Investigating; Asthma

Asthma is the commonest chronic lung disease in the UK. It affects all age groups and significantly impacts on quality of life, schooling and work. For most it requires lifelong treatment with drugs and uncertainty, due to the variable nature of the disease. Little is known how factors initiate the disease in early life or impact over the life course of the disease. This programme is centred on studying the life course of asthma, focusing on underlying mechanisms that may lead to disease persistence and progression and how different environmental factors exert influence.Our research focuses on the human asthma and involves sampling the airways to evaluate on-going tissue events and to obtain airway cells that can be studied in the laboratory under different conditions of exposure. We believe that the airways lining (epithelium) plays a major role in interacting with the environment and, in asthma, expresses signals that promote abnormal inflammation within the airways and induce structural changes (scarring) that alters their flexibility. We have called this dynamic interaction between the epithelium and the deeper airway wall structures the Epithelial Mesenchymal Trophic Unit (EMTU). Our research focuses on understanding how this EMTU is activated in asthma of differing severity and stages of disease. Recognising that most asthma has its origin in the first few years of life, undergoes major changes during childhood and adolescence in which over half ?grow out? of their diseases and adopts characteristics of becoming irreversible in some adults, we have constructed our 5 year programme in 3 stages: (i) In young children at the onset of disease we will use our cell culture systems in the presence and absence of virus, allergen and tobacco smoke exposure to seek differences in the way the epithelium communicates with underlying cells in the EMTU; ii) In teenagers from our Isle of Wight cohort, that has been extensively characterised in relationship to asthma from birth to the age of 18 years, we will assess activation of the EMTU in those with persistent asthma and those who have ?grown out? of asthma; and (iii) In adults with established asthma we determine how the scarring affects the stiffness of the airway wall and whether repeated airway narrowing contributes to and can account for the loss of treatment response in such asthmatics.This research will identify much needed new targets in disease prevention and treatment high up in the causal disease pathways.

哮喘是英国最常见的慢性肺部疾病。它影响所有年龄段，并对生活质量，学校和工作产生重大影响。对于大多数人来说，由于疾病的性质可变，因此需要用药物和不确定性治疗。知之甚少，因素如何在早期生命中引发该疾病或在疾病的生活过程中影响。该计划集中在研究哮喘的生命过程中，重点关注可能导致疾病持久性和进展的潜在机制，以及不同的环境因素如何发挥影响。我们认为，气道衬里（上皮）在与环境相互作用中起着重要作用，并且在哮喘中表达了促进气道内异常炎症的信号，并引起结构变化（疤痕），从而改变了它们的灵活性。我们称上皮和较深的气道壁之间的这种动态相互作用是上皮间质营养单元（EMTU）。我们的研究重点是了解这种EMTU在不同严重程度和疾病阶段的哮喘中如何激活。认识到大多数哮喘在生命的头几年起起源，在儿童时期和青春期发生了重大变化，超过一半？在某些成年人中，它们的疾病并采用了变得不可逆转的特征，我们已经在3个阶段构建了我们的5年计划：（i）在疾病发作时，在幼儿中，我们将在病毒，过敏原和烟草烟雾的存在下使用我们的细胞培养系统，以与上皮相处的emplys smoge smoke smoke the Emtuce cell inemtu smecly segrance seking neemtu cell in emtu cell in emtu cell in emtube cell; ii）在我们怀特岛队列的青少年中，从出生到18岁的哮喘的关系中，这是广泛的特征，我们将评估EMTU在患有持续性哮喘的人中的激活，并且已经成长了？哮喘（iii）在患有已建立哮喘的成年人中，我们确定疤痕如何影响气道壁的僵硬，以及反复的气道狭窄是否有助于并可以解释哮喘患者的治疗反应丧失。这项研究将确定在因果疾病途径中急需的疾病预防和治疗方面的急需新目标。