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疾病的结果范围很高，这种个体与个体的变异性很差理解。克隆造血是一种普遍的，与年龄相关的疾病，是由造血细胞中的各种体细胞突变，可以导致其克隆扩增。这些突变克隆损坏免疫细胞功能，并通过细胞因子失调。拟议的研究将调查克隆造血的假设是一种血液学宿主因子使人易于发展严重的Covid-19疾病。通过协作肯尼斯·沃尔什（Kenneth Walsh）博士学位之间的努力（UVA）和Christopher Defilippi M.D.（Inova）拟议的研究将探索克隆造血对免疫系统的改变的可能性明显炎症反应的临床实验室措施，心脏损伤的生化证据和 COVID-19感染患者的临床结局差。患者将同意并在Inova招收北弗吉尼亚州的医院系统每年在华盛顿为超过200万人提供服务 D.C大都会区，有大量住院的Covid-19阳性患者。入学时，生物测量将被收集和存放。临床数据将从电子病历中提取，并存储在研究表中的研究表格捕获软件。 DNA将发送给UVA沃尔什博士的实验室用于分析克隆造血。 INOVA组的DNA将在UVA处理以评估克隆通过靶向错误校正的DNA测序通过造血作用。该分析采用了一个丰富面板捕获感兴趣的驱动基因和用DNA条形码构建库。接下来跟随深处生成DNA测序，采用生物信息学平台来区分真实的变体和噪声一个特定的外显子位置。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，临床结局和炎症标志之间是否存在关联和心脏损伤。