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

哮喘、过敏和呼吸道感染（RTI）是儿童和成年期最常见的疾病。虽然它们是密不可分的，但控制感染，过敏和哮喘发展和哮喘发作风险增加之间关系的免疫机制知之甚少。因此，在过去的50年里，哮喘（特别是哮喘发作）的治疗进展甚微。这些疾病的严重程度和风险随着年龄的变化而变化，特别是在青春期发生的变化很大-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名儿童的知识，从出生开始寻找哮喘和过敏的风险因素，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。这将使我们更好地了解为什么儿童会患上哮喘，以及这种疾病在青春期是如何变化的，我们希望为可能的药物治疗确定新的靶点。我们将结合联合收割机在出生队列/生命过程研究、呼吸道感染、先天免疫、我们将利用新的分析技术来确定与RTI易感性增加相关的机制，这些RTI易感性增加导致哮喘发展和哮喘发作的易感性增加。从8岁到青春期（11岁和14岁），到成年（18岁），并将他们暴露于这些传染性病原体并测量反应。我们将研究青春期身体如何改变其产生过敏原抗体的方式，通过在上述时间点测量IgE抗体，我们将研究基因序列的变化如何与对感染的免疫力以及过敏原我们将使用新的计算技术分析数据，认识到这些系统是高度复杂的，相互作用，而不是孤立地运行。通过研究在分子水平上的重要调节机制，我们将确定治疗或预防哮喘发展，哮喘发作和RTI的潜在目标。潜在的治疗靶点将在申请人熟知的人原代细胞和体内研究中使用分子细胞生物学技术进行验证。

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.