MICA: Phenotyping immune responses in asthma and respiratory infections - a systems approach to understanding changes from childhood to adulthood

MICA：哮喘和呼吸道感染的表型免疫反应——一种了解从儿童到成年变化的系统方法

• 批准号: MR/L012693/1
• 负责人: Sebastian Johnston
• 金额: $ 284.82万
• 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: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL012693%2F1
• 关键词: MICA; Phenotyping; immune; responses; asthma

Asthma, allergies and respiratory tract infections (RTIs) are the most common diseases in childhood and adulthood. Although they are inextricably linked, the immune mechanisms governing the relationships between the infection, allergy and increased risk of asthma development and asthma attacks are very poorly understood. Consequently, there have been few advances in treatments for asthma (and in particular asthma attacks) in the last 50 years. Severity and risk of these conditions varies substantially with age, with in particular large changes occurring through puberty - before puberty boys have increased risk/severity of asthma and RTIs, while after puberty females are at substantially greater risk.Impaired immune responses to viruses are strongly implicated in increased susceptibility to virus infections in asthma, but the mechanisms behind these impaired responses are unknown. The mechanisms explaining increased susceptibility to bacterial infections in asthma are unknown.We propose a novel approach aiming to understand the mechanisms of interplay between asthma, allergies and innate immune responses to viruses and bacteria. Building on knowledge we already have of a population of 1000 children, followed since birth to look for risk factors for asthma and allergies, we will collect new data (outlined below) and by using a systems approach to apply innovative computational statistical methods to the data we will study the interactions between host response to infections, allergens and asthma. This will give a better understanding of why children develop asthma, how this changes through puberty and we hope to identify new targets for possible drug therapies. We will combine world-leading expertise in birth cohort/life course studies, respiratory infections, innate immunity, asthma and allergies and computational analysis We will utilise novel analytical techniques to identify mechanisms related to increased susceptibility to RTIs causing increased susceptibility to asthma development and asthma attacksWe will investigate changes in the way the body handles infection from bacteria and viruses from childhood by taking blood cells from the body at age 8 years, through puberty (ages 11 & 14), to adulthood (age 18) and exposing them to these infectious agents and measuring the responseWe will investigate how through puberty the body changes in the way it makes antibodies to allergens, by measuring IgE antibodies at the time points aboveWe will investigate how changes in gene sequences are associated with immunity to infection and to allergens. We will analyse the data using novel computational techniques, recognising that these systems are highly complex and interact with each other, and do not operate in isolationBy studying mechanisms which are important regulators at a molecular level, we will identify potential targets for treatment or prevention of asthma development, asthma attacks and RTIs. Potential therapeutic targets will be validated using molecular cell biology techniques in human primary cells and in vivo studies in which the applicants are well versed.

哮喘、过敏和呼吸道感染（RTIs）是儿童和成年期最常见的疾病。尽管它们之间有着千丝万缕的联系，但控制感染、过敏、哮喘发展和哮喘发作风险增加之间关系的免疫机制却知之甚少。因此，在过去的50年里，哮喘（尤其是哮喘发作）的治疗几乎没有什么进展。这些疾病的严重程度和风险随年龄变化很大，青春期发生的变化尤其大——青春期前，男孩患哮喘和呼吸道感染的风险/严重程度增加，而青春期后，女性患哮喘和呼吸道感染的风险更大。对病毒的免疫反应受损与哮喘患者对病毒感染的易感性增加密切相关，但这些受损反应背后的机制尚不清楚。哮喘患者对细菌感染易感性增加的机制尚不清楚。我们提出了一种新的方法，旨在了解哮喘，过敏和对病毒和细菌的先天免疫反应之间的相互作用机制。基于我们已经拥有的1000名儿童人口的知识，从出生开始寻找哮喘和过敏的危险因素，我们将收集新的数据（如下所述），并通过使用系统方法将创新的计算统计方法应用于数据，我们将研究宿主对感染，过敏原和哮喘的反应之间的相互作用。这将使我们更好地理解儿童患哮喘的原因，以及这种情况在青春期是如何变化的，我们希望找到可能的药物治疗的新目标。我们将结合世界领先的出生队列/生命历程研究、呼吸道感染、先天免疫、我们将利用新的分析技术来确定与RTIs易感性增加相关的机制，从而导致哮喘发展和哮喘发作的易感性增加。我们将通过从8岁到青春期（11岁和14岁）从体内提取血细胞来研究人体处理细菌和病毒感染的方式的变化。到成年期（18岁），让他们接触这些传染性病原体，并测量他们的反应。我们将通过测量上述时间点的IgE抗体，研究青春期身体产生过敏原抗体的方式是如何变化的。我们将研究基因序列的变化是如何与对感染和过敏原的免疫联系起来的。我们将使用新颖的计算技术分析数据，认识到这些系统是高度复杂的，彼此相互作用，并且不是孤立地运行。通过研究分子水平上重要的调节机制，我们将确定治疗或预防哮喘发展，哮喘发作和rti的潜在靶点。潜在的治疗靶点将使用分子细胞生物学技术在人原代细胞和申请人精通的体内研究中进行验证。

项目成果

Attenuating COVID-19 infection and inflammation: Lessons from asthma.

减轻 COVID-19 感染和炎症：哮喘的教训。

• DOI: 10.1111/resp.13961
• 发表时间: 2020
• 期刊: Respirology (Carlton, Vic.)
• 作者: Bardin PG

Modeling Wheezing Spells Identifies Phenotypes with Different Outcomes and Genetic Associates.

• DOI: 10.1164/rccm.202108-1821oc
• 发表时间: 2022-04-15
• 期刊: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
• 影响因子: 24.7
• 作者: Haider, Sadia;Granell, Raquel;Curtin, John;Fontanella, Sara;Cucco, Alex;Turner, Stephen;Simpson, Angela;Roberts, Graham;Murray, Clare S.;Holloway, John W.;Devereux, Graham;Cullinan, Paul;Arshad, Syed Hasan;Custovic, Adnan
• 通讯作者: Custovic, Adnan

Machine learning to identify pairwise interactions between specific IgE antibodies and their association with asthma: A cross-sectional analysis within a population-based birth cohort.

• DOI: 10.1371/journal.pmed.1002691
• 发表时间: 2018-11
• 期刊: PLoS medicine
• 影响因子: 15.8
• 作者: Fontanella S;Frainay C;Murray CS;Simpson A;Custovic A
• 通讯作者: Custovic A