Asthma Endotypes: Mechanisms and Consequences for Airway Epithelium and Mucus

哮喘内型：气道上皮和粘液的机制和后果

• 批准号: 10371127
• 负责人: David J Erle
• 金额: $ 179.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-08 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371127
• 关键词: 2019-nCoV; Adult; Affect; Age; Aspirate substance; Asthma; Biological; Biological Assay; COVID-19; COVID-19 pandemic; COVID-19 patient; Case Fatality Rates; China; Chronic; Clinical; Clinical Research; Clinical Trials; Communities; Coronavirus; DNA Sequencing Facility; Development; Diabetes Mellitus; Disease; Disease Outcome; Elements; Enrollment; Environmental Risk Factor; Family; General Hospitals; Genetic; Genetic Risk; Health; Healthcare Systems; Hypertension; Immune System Diseases; Immune response; Immunologics; Immunophenotyping; Individual; Institution; Intervention; Investigation; Laboratories; Lung diseases; Medical; Medical center; Metagenomics; Methods; Mucous body substance; Myocardial Ischemia; National Institute of Allergy and Infectious Disease; Nature; Onset of illness; Outcome; Participant; Pathogenicity; Patients; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Phage Display; Phage ImmunoPrecipitation Sequencing; Pharmaceutical Preparations; Pneumonia; Prognostic Marker; Recurrence; Resources; Risk Factors; SARS-CoV-2 infection; Sample Size; Sampling; San Francisco; Serology; Serum; Severity of illness; Site; Therapeutic Agents; Variant; Viral Load result; Virus; airway epithelium; base; biomarker development; clinical center; clinical risk; cohort; comorbidity; design; effective therapy; endotracheal; global health; health care availability; improved; inclusion criteria; member; mortality; neutralizing antibody; neutralizing vaccine; next generation sequencing; novel; novel therapeutics; novel virus; pandemic disease; pathogen; peripheral blood; prospective; respiratory; response; social structure; therapeutic target; transcriptome sequencing; trauma centers; welfare

PROJECT SUMMARY/ABSTRACT COVID-19, the pandemic illness caused by the novel virus SARS-CoV-2, is a serious respiratory illness that has high infectivity and a mortality rate that varies from <1% to up to 20% depending on underlying risk factors. Indeed, disease severity varies markedly based on recognized clinical risk factors (age and co-morbidities). The biological underpinnings of this clinical variability are unknown but likely relate to variation in both the virus and the host response. A detailed understanding of the risk factors for severe disease, including genetic and environmental factors and the nature of the host immunological response, is essential for the development of prognostic biomarkers and effective therapies. To meet this urgent need we propose to help develop and to participate in the IMPACC multi-center longitudinal clinical study of hospitalized patients with COVID-19 and to immunophenotype participants using shared immunological methods that will be designed an carried out by core laboratories at UCSF and at other participating institutions. Our specific aims are 1) to develop a prospective observational convenience cohort of adult subjects hospitalized with known or presumptive COVID-19, 2) to use this cohort to describe the relationship between specific immunologic assessments and clinical course of COVID-19 in hospitalized patients, and 3) to implement three core laboratories at UCSF to support immunophenotyping in this multicenter cohort. These core laboratories will perform bulk RNA sequencing of blood peripheral blood mononuclear cells (PBMC), bulk metagenomic next-generation sequencing (mNGS) on endotracheal aspirate samples, and serologic phage display assays (PhIP-Seq). Successful completion of these aims will yield critical information regarding the relationship between viral load, host immunological responses, and poor clinical outcomes that are urgently needed for biomarker development and rational therapeutic targeting. In addition, the cellular samples banked in this study may directly contribute to the development of neutralizing antibodies and vaccine strategies that will be our ultimate defense against recurrence of this extraordinary pandemic. A rapid and robust scientific and medical response of the type proposed by the NIAID and the academic community in this consortium is an essential element of a broad response required to protect the health and well-being of all individuals, our health care system, and the broader social structures that maintain global health and welfare.

项目总结/摘要 COVID-19是由新型病毒SARS-CoV-2引起的大流行性疾病，是一种严重的呼吸道疾病， 具有高传染性，根据潜在的风险因素，死亡率从<1%到高达20%不等。 事实上，疾病的严重程度根据公认的临床风险因素（年龄和合并症）而明显不同。 这种临床变异性的生物学基础尚不清楚，但可能与病毒的变异有关。 和宿主的反应。详细了解严重疾病的风险因素，包括遗传和 环境因素和宿主免疫反应的性质，对发展至关重要。 预后生物标志物和有效治疗。为了满足这一迫切需要，我们建议帮助发展和 参与IMPACC多中心COVID-19住院患者纵向临床研究， 免疫表型参与者使用共享的免疫学方法，将由 在UCSF和其他参与机构的核心实验室。我们的具体目标是：（1）发展一个 因已知或推定的疾病住院的成人受试者的前瞻性观察便利队列 COVID-19，2）使用该队列描述特异性免疫学评估与 住院患者的COVID-19临床过程，以及3）在UCSF实施三个核心实验室， 支持本多中心队列的免疫表型分析。这些核心实验室将进行批量RNA 血液外周血单核细胞（PBMC）测序，下一代批量宏基因组 气管内抽吸物样品的测序（mNGS）和血清学噬菌体展示测定（PhIP-Seq）。 成功完成这些目标将产生关于病毒载量， 宿主免疫反应和临床结果差，迫切需要生物标志物 开发和合理的治疗靶向。此外，本研究中储存的细胞样本可能 直接有助于开发中和抗体和疫苗策略，这将是我们最终的目标。 防止这种特殊的流行病再次发生。迅速而有力的科学和医学反应 由NIAID和该联盟中的学术界提出的类型是一个基本要素， 保护所有人的健康和福祉，我们的医疗保健系统， 维护全球健康和福利的更广泛的社会结构。