Examining COVID-19 in Down Syndrome Patients Using Human iPSC-Derived Organoids

使用人类 iPSC 衍生的类器官检查唐氏综合症患者的 COVID-19

基本信息

批准号：
10241207
负责人：
Lei Stanley Qi
金额：
$ 66.88万
依托单位：
STANFORD UNIVERSITY
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：
2021-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241207
关键词：
2019-nCoV 3-Dimensional A549 Address Administrative Supplement Alveolar Macrophages Arrhythmia Biology Biometry Blood Vessels COVID-19 COVID-19 health disparity COVID-19 mortality COVID-19 pandemic COVID-19 patient Cardiac Cardiac Myocytes Cardiovascular system Case Fatality Rates Cause of Death Cell Death Cell Line Cells Cessation of life Chronic lung disease Clinical Data Detection Disease Progression Disease susceptibility Down Syndrome Electrophysiology (science)Endothelial Cells Epithelial Cells Event Experimental Models Familial Hypertrophic Cardiomyopathy Fibroblasts Functional disorder Genes Genomics Heart Heart Injuries Hospitalization Human Hypertension Immune response Immunology Individual Inflammation Inflammatory Inflammatory Response Knowledge Lead Life Lung Medical Metabolic Diseases Modeling Molecular Molecular Profiling Myocarditis Obesity Organ Organoids Oxidative Stress Patients Peripheral Phenotype Pulmonary Inflammation Qi Resources Respiratory Failure Risk SARS-CoV-2 infection Secondary to Serum Structure Test Result Testing Tissues Troponin Tungsten Viral Virus Virus Diseases Wing biobank cell type chemokine coronavirus disease cytokine endothelial dysfunction genome editing health disparity induced pluripotent stem cell multidisciplinary novel coronavirus profiles in patients respiratory response severe COVID-19 single-cell RNA sequencing stem cell biology transcriptomics vascular injury viral myocarditis virology

项目摘要

Project Summary Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has infected more than 20 million people worldwide as of August 2020 and significantly altered our way of life. Despite its relative low case-fatality rate, the new coronavirus disease (COVID-19) can cause serious illness in people with pre-existing conditions like individuals with Down Syndrome (DS). It is projected that SARS-CoV-2 can cause 8.9-fold increased risk of COVID-19 related hospitalization and deaths in DS patients, yet we have limited experimental resource to understand the basic mechanisms underlying differential disease susceptibility and progression. Here we propose to use i) human induced pluripotent stem cells (iPSCs), ii) tissue-like organoids, iii) live SARS-CoV-2 virus and iv) serum collected from COVID-19 patients. We will generate 40 iPSC-derived organoids from DS and non-DS individuals and infect them with SARS-CoV-2. We will focus on two major clinical manifestations commonly observed in COVID-19 patients with critical conditions: viral myocarditis and severe pulmonary inflammation. For Aim 1, we will generate cardiac organoids composing of iPSC-derived cardiomyocytes, endothelial cells, and cardiac fibroblasts to assess their functional and structural changes after SARS-CoV-2 infection. For Aim 2, we will generate lung organoids composing of iPSC-derived lung epithelial cells, endothelial cells, alveolar macrophages, and identify an inflammatory signature after SARS-CoV-2 infection. For both Aims, we will perform single cell RNA sequencing to identify differential gene response among different cell types which contribute to phenotypic changes following SARS-CoV-2 infection.

项目概要严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 大流行已感染超过 2000 万人截至 2020 年 8 月，全世界人民都受益匪浅，并显着改变了我们的生活方式。尽管病死率相对较低率，新型冠状病毒病 (COVID-19) 可能会导致已有疾病的人患上严重疾病就像患有唐氏综合症 (DS) 的人一样。预计 SARS-CoV-2 可能导致感染风险增加 8.9 倍 DS 患者中与 COVID-19 相关的住院和死亡，但我们的实验资源有限了解不同疾病易感性和进展的基本机制。在这里我们建议使用 i) 人类诱导多能干细胞 (iPSC)，ii) 组织样类器官，iii) 活 SARS-CoV-2 病毒和 iv) 从 COVID-19 患者收集的血清。我们将从 DS 生成 40 个 iPSC 衍生的类器官，非 DS 个体并用 SARS-CoV-2 感染他们。我们将重点关注两个主要的临床表现常见于病情危重的 COVID-19 患者：病毒性心肌炎和严重肺部感染炎。对于目标 1，我们将生成由 iPSC 衍生的心肌细胞组成的心脏类器官，内皮细胞和心脏成纤维细胞，以评估 SARS-CoV-2 后其功能和结构的变化感染。对于目标 2，我们将生成由 iPSC 衍生的肺上皮细胞、内皮细胞组成的肺类器官细胞、肺泡巨噬细胞，并识别 SARS-CoV-2 感染后的炎症特征。为了这两个目标，我们将进行单细胞 RNA 测序，以确定不同细胞类型之间的差异基因反应有助于 SARS-CoV-2 感染后的表型变化。