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喘息性疾病，并增加这些儿童 继续发展成哮喘。现在人们认识到，哮喘在儿童中并不是平等的。有 哮喘有不同形式，患有过敏的喘息儿童患哮喘的风险最高。是 目前尚不清楚为什么哮喘和过敏的儿童更容易感染呼吸道病毒 感染，更有可能患上哮喘。然而，从我们以前的研究中得到的一个重要线索是， 与病毒诱导的喘息风险和保护相关的免疫因子可在局部发现 呼吸道和肺部，以及全身性的血液和骨髓中。这表明我们的总体 假设决定对病毒诱导的喘鸣易感性的免疫机制 通过肺-血-骨髓轴局部和全身地给药。在这里，我们将研究全身免疫 有或没有喘息、过敏性炎症或两者兼而有之的儿童对病毒的反应。这项研究将 需要在存在或不存在病毒的情况下培养来自儿童的血液来源的免疫细胞。分子 分析技术将被用来表征免疫反应的病毒在分辨率 单个细胞，并将在有或无喘息的儿童组中比较和对比这些反应 和/或过敏性炎症。我们假设哮喘的风险是由生物学平衡决定的。 控制对病毒的免疫反应的两种免疫因子的活性：干扰素调节因子7（IRF 7） 和高亲和力免疫球蛋白E受体亚基γ（FCER 1G）。我们还假设， 一群高度特化的免疫细胞称为树突状细胞，控制着IRF 7和FCER 1G的平衡 活动这项研究的发现很重要，因为哮喘影响13个美国人中的1个，是最重要的。 儿童常见的慢性病。在美国，每年哮喘占到 100万次全科医生就诊，150多万次急诊就诊，近20万次出院 从医院的住院病人护理。此外，在美国，每天约有11人死于哮喘。 States.了解决定哮喘风险的免疫学和分子因素将铺平道路 开发新的方法来治疗或预防哮喘，并减少这种疾病的总体负担。 疾病对儿童及其家庭的影响。