Clonal hematopoiesis and severity of COVID-19 disease

克隆造血和 COVID-19 疾病的严重程度

基本信息

批准号：
10196497
负责人：
KENNETH WALSH
金额：
$ 33.66万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196497
关键词：
2019-nCoV Acute Age Area Bar Codes Biochemical Bioinformatics Blood COVID-19 COVID-19 patient COVID-19 severity Cardiac Cardiovascular Diseases Cell physiology Cells Child Clinical Clinical Data Clinical Research Clonal Hematopoietic Stem Cell Computer software Computerized Medical Record Consent DNA DNA sequencing Data Dependence Development Diabetes Mellitus Disease Doctor of Medicine Doctor of Philosophy Elderly Enrollment Exhibits Gender Genes Heart Injuries Hematology Hematopoiesis Hematopoietic Hospitalization Hospitals Hypertension IL6 Signaling Pathway Immune Immune response Immune system Individual Inflammaging Inflammatory Response Integration Host Factors Intensive Care Interleukin-1 beta Interleukin-6 Laboratories Lead Leukocytes Libraries Location Measures Mechanical ventilation Mediating Middle East Respiratory Syndrome Molecular Mutation Noise Outcome Patients Persons Plasma Precancerous Conditions Predisposing Factor Process RNA Race Research SARS-CoV-2 infection SARS-CoV-2 positive Services Severe Acute Respiratory Syndrome Signal Transduction Somatic Mutation Syndrome System Testing Trans-Omics for Precision Medicine Troponin Variant Virginia Washington Work age related cardiovascular disorder risk cohort cytokine cytokine release syndrome electronic data experimental study gene cloning hematopoietic stem cell expansion individual variation inflammatory marker interest mortality mutant myocardial injury next generation pathogenic virus prospective respiratory response severe COVID-19

项目摘要

SUMMARY COVID-19 disease has a diverse range of outcomes, and this individual-to-individual variability is poorly understood. Clonal hematopoiesis is a prevalent, age-associated condition that arises from the accumulation of various somatic mutations in hematopoietic cells and can lead to their clonal amplification. These mutant clones corrupt immune cell function and contribute to mortality and increased cardiovascular disease risk through cytokine dysregulation. The proposed research will investigate the hypothesis that clonal hematopoiesis is a hematologic host factor that predisposes persons to develop severe COVID-19 disease. Through a collaborative effort between Kenneth Walsh Ph.D. (UVA) and Christopher deFilippi M.D. (Inova) the proposed research will explore the possibility that clonal hematopoiesis-mediated alterations to the immune system are associated with clinical laboratory measures of a marked inflammatory response, biochemical evidence of cardiac injury and poor clinical outcomes in patients with COVID-19 infection. Patients will be consented and enrolled at the Inova hospital system in northern Virginia that delivers service to more than 2 million people per year in the Washington, D.C metro area with a large volume of hospitalized COVID-19 positive patients. Upon enrollment, biospecimens will be collected and banked. Clinical data will be extracted from the electronic medical record and stored in research form in Research Electronic Data Capture software. DNA will be sent to Dr. Walsh’s laboratory at UVA for analysis of clonal hematopoiesis. DNA from the Inova group will be processed at UVA to assess clonal hematopoiesis via targeted, error-corrected DNA sequencing. This analysis employs an enrichment panel to capture driver genes of interest and the construction of libraries with DNA barcodes. Following deep next generation DNA sequencing, a bioinformatic platform is employed to distinguish true variant calls from noise at a particular exonic location. These data on clonal hematopoiesis will then be shared with the team at Inova to test whether there are associations between somatic mutations, clinical outcome, and markers of inflammation and cardiac injury.

概括 COVID-19 疾病有多种结果，而且这种个体间差异很小克隆性造血是一种普遍存在的、与年龄相关的疾病，是由细胞积累引起的。造血细胞中的各种体细胞突变可以导致它们的克隆扩增。破坏免疫细胞功能，导致死亡并增加心血管疾病风险拟议的研究将调查克隆造血是一种细胞因子失调的假设。通过合作，使人容易患上严重的 COVID-19 疾病的血液宿主因素。 Kenneth Walsh 博士 (UVA) 和 Christopher deFilippi 医学博士 (Inova) 的共同努力，拟议的研究将探索克隆造血介导的免疫系统改变与以下因素相关的可能性：显着炎症反应的临床实验室测量、心脏损伤的生化证据和 COVID-19 感染患者临床结果不佳的患者将获得 Inova 的同意并入组。弗吉尼亚州北部的医院系统每年为华盛顿超过 200 万人提供服务，拥有大量住院 COVID-19 阳性患者的华盛顿都会区入组后，生物样本。临床数据将从电子病历中提取并存储在其中。研究电子数据捕获软件中的研究表格将被发送到沃尔什博士在 UVA 的实验室。用于克隆造血分析的 Inova 组 DNA 将在 UVA 进行处理以评估克隆。通过有针对性的、纠错的 DNA 测序进行造血。该分析采用富集面板来进行。捕获感兴趣的驱动基因并使用 DNA 条形码构建文库。一代 DNA 测序，采用生物信息平台来区分真正的变异调用和噪音然后，这些有关克隆造血的数据将与 Inova 的团队共享，测试体细胞突变、临床结果和炎症标志物之间是否存在关联和心脏损伤。