Systemic and intercellular gene networks underlying RV-induced airways disease

RV 诱发气道疾病的全身和细胞间基因网络

• 批准号: 10741518
• 负责人: Anthony Bosco
• 金额: $ 26.86万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741518
• 关键词: 2 year old; Accident and Emergency department; Acute; Adolescence; Affect; Affinity; Age; Airway Disease; Allergens; Allergic inflammation; American; Animal Model; Animals; Antiviral Response; Asthma; Back; Biological; Birth; Blood; Bone Marrow; Breathing; Bronchiolitis; Cells; Child; Childhood Asthma; Chronic; Chronic Disease; Data; Dendritic Cells; Development; Early Mobilizations; Eosinophilia; Epithelial Cells; Equilibrium; Exploratory/Developmental Grant; Family; Growth; Growth Factor; Hospitals; Human; Hypersensitivity; IgE Receptors; Immune; Immune response; Immunologic Factors; Immunologics; Infant; Infection; Inflammation; Interferon Type I; Interferons; Life; Longitudinal Studies; Lung; Mediating; Modeling; Molecular; Molecular Profiling; Nasal Lavage Fluid; Natural Immunity; Pathologic; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Population; Predisposing Factor; Predisposition; Pulmonary Function Test/Forced Expiratory Volume 1; Rat Strains; Rattus; Recording of previous events; Recurrence; Research; Resolution; Rhinovirus; Risk; Sampling; Schools; Signal Transduction; Small Interfering RNA; Sputum; Structure; Systems Biology; T-Cell Activation; T-Lymphocyte; Technology; Testing; Time; Tissues; Translating; United States; Up-Regulation; Variant; Viral; Viral Respiratory Tract Infection; Virus; Visit; Wheezing; airway epithelium; airway inflammation; airway obstruction; antiviral immunity; asthma exacerbation; asthma prevention; asthmatic; atopy; burden of illness; cohort; design; early onset; gene network; high risk; inpatient service; intercellular communication; interferon regulatory factor-7; knock-down; molecular phenotype; monocyte; nasal swab; neutrophil; novel; novel strategies; prevent; prospective; pulmonary function; recruit; respiratory; response; trait; transcriptomics

Respiratory viral infections trigger wheezing illnesses in children and increase the risk that these children will go on to develop asthma. It is now recognized that asthma is not created equal among children. There are different forms of asthma, and risk for asthma is highest among wheezing children who also have allergies. It is currently not well understood why children with wheezing and allergies are more susceptible to respiratory viral infections and more likely to develop asthma. However, an important clue from our previous studies is that the immune factors that are associated with risk versus protection to virus-induced wheezing can be found locally in the airways and lung and also systematically in the blood and bone marrow. This suggested our overarching hypothesis that the immunological mechanisms that determine susceptibility to virus-induced wheezing operate both locally and systemically through a lung-blood-bone marrow axis. Here, we will study systemic immune responses to viruses in children with or without wheezing, allergic inflammation, or both. The research will entail culturing blood-derived immune cells from the children in the presence or absence of a virus. Molecular profiling technologies will be employed to characterize immune responses to the virus at the resolution of single cells, and the responses will be compared and contrasted in groups of children with or without wheezing and/or allergic inflammation. We hypothesize that risk for asthma is determined by the balance of the biological activity of two immune factors that control immune responses to viruses: Interferon regulatory factor 7 (IRF7) and the high-affinity immunoglobulin E receptor subunit gamma (FCER1G). We additionally hypothesize that a highly specialized population of immune cells called dendritic cells control the balance of IRF7 and FCER1G activity. The findings from this study are important because asthma affects 1 in 13 Americans and is the most common chronic disease among children. Each year in the United States, asthma accounts for more than 5 million GP visits, more than 1.5 million visits to the emergency department, and almost 200,000 discharges from hospital inpatient care. Moreover, approximately 11 people die from asthma every day in the United States. Understanding the immunological and molecular factors that determine asthma risk will pave the way for the development of new approaches to treat or prevent asthma and reduce the overall burden of this disease on children and their families.

呼吸道病毒感染会引发儿童的喘息疾病，并增加这些儿童的风险 继续发展哮喘。现在已经认识到，儿童之间的哮喘不是平等的。有 在喘息的儿童中，不同形式的哮喘和哮喘的风险最高。这是 目前不太了解为什么患有喘息和过敏的孩子更容易受到呼吸病毒的影响 感染，更有可能发展哮喘。但是，我们以前研究的一个重要线索是 可以在本地找到与风险与保护病毒引起的喘息有关的免疫因子 在气道和肺中，还系统地在血液和骨髓中。这表明了我们的总体 假设确定对病毒诱发喘息易感性的免疫机制作用 通过局部和系统地通过肺骨骨髓轴。在这里，我们将研究系统性免疫 患有或没有喘息，过敏性炎症或两者的儿童病毒的反应。研究将 在存在或不存在病毒的情况下，需要从儿童培养血液衍生的免疫细胞。分子 分析技术将被用来表征对病毒的免疫反应。 单个单元格，将在有或没有喘息的儿童组中比较和对比 和/或过敏性炎症。我们假设哮喘的风险取决于生物学的平衡 控制病毒免疫反应的两个免疫因子的活性：干扰素调节因子7（IRF7） 以及高亲和力免疫球蛋白E受体亚基伽马（FCER1G）。我们还假设 高度专业的免疫细胞种群称为树突状细胞控制IRF7和FCER1G的平衡 活动。这项研究的发现很重要，因为哮喘影响了13个美国人中的1个，并且是最重要的 儿童常见的慢性病。每年在美国，哮喘占5个以上 百万的全科医生访问，超过150万次急诊室的访问，近200,000次出院 从医院住院护理。此外，大约有11人死于联合的哮喘 国家。了解确定哮喘风险的免疫学和分子因素将铺平道路 为了开发新的方法来治疗或预防哮喘并减轻了总体负担 儿童及其家人的疾病。