Uncover mechanisms underlying the development of chronic lung sequelae post COVID-19

揭示 COVID-19 后慢性肺部后遗症发生的机制

基本信息

批准号：
10734747
负责人：
Jie Sun
金额：
$ 72.03万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734747
关键词：
2019-nCoV Acute Acute Disease Address Adult Age Years Animal Model Automobile Driving Blood Bronchoalveolar Lavage Fluid CD8-Positive T-Lymphocytes CD8B1 gene COVID-19 Characteristics Chronic Chronic Lung Injury Chronic lung disease Clinical Clinical Research Development Dyspnea Enrollment Exertion Exhibits Fatigue Fibrosis Future Goals Hospitalization Human Human Characteristics Hypoxia Immune Immune response Immunology Impairment Individual Infection Intervention Link Long COVID Longitudinal cohort Lung Lung immune response Memory Modeling Molecular Morbidity - disease rate Mus Pathologic Patients Physiological Population Population Control Post-Acute Sequelae of SARS-CoV-2 Infection Pulmonary function tests Resolution Respiratory Signs and Symptoms Role SARS-CoV-2 infection Sample Size Science Shortness of Breath Study models Survivors System Systems Biology T cell response T-Lymphocyte Subsets Testing Therapeutic Intervention Time Tissues Validation Viral Viral reservoir X-Ray Computed Tomography aged chest computed tomography clinical examination cohort data integration druggable target follow-up high risk human data insight long-term sequelae mortality mouse model new therapeutic target pandemic disease pathogen post-COVID-19 predictive marker preventive intervention pulmonary function respiratory response targeted treatment therapeutic target tissue resident memory T cell tool trait

项目摘要

Project Summary Apart from the acute illness caused by SARS-CoV-2, it is now clear that a significant percentage of patients develop long-term conditions post COVID-19, including systemic and respiratory symptoms. Given the catastrophic spread of SARS-CoV-2 infection globally, there are many individuals that recover from acute COVID-19 and develop permanent impairment in lung function which can cause exertional dyspnea, fatigue (due to chronic hypoxia), and other limitations. This number will become even larger as the pandemic continues to progress. Therefore, there is an urgent need to understand the mechanisms underlying the development of chronic respiratory sequelae of COVID-19 to develop preventive and therapeutic interventions. In this application, we aim to unravel the driving mechanisms and identify potential therapeutic targets of chronic lung sequelae following COVID-19. To achieve this goal, we propose two Specific Aims (SA) for the study. SA 1. Decipher cellular and molecular traits underlying chronic lung sequelae post-acute COVID-19. We will enroll a group of COVID-19 convalescents that are expected to develop chronic lung sequelae after prior severe acute disease and a control population that completely recovered from previous mild or non-symptomatic COVID-19 infection. We will conduct comprehensive clinical examination supplemented by quantitative chest CT imaging and pulmonary function testing to determine clinical and pathophysiological characteristics of the two populations. We will collect longitudinal blood and bronchoalveolar lavage fluid (BAL) to obtain immune, molecular, and viral profiles in COVID-19 convalescents and controls. This unique approach integrating systemic and respiratory clinical, pathophysiological, cellular, molecular, and viral profiles of control or COVID- 19 convalescents will be highly compelling for future druggable target discovery. SA2. Model and validate targets of chronic lung sequelae post-acute COVID-19 in an animal model. We will establish a mouse model of chronic lung sequelae post-acute COVID-19. We will characterize systemic and respiratory host cellular and molecular responses in the model. integrate mouse and human data for validation of mechanistic links and discovery of new insights and/or targets for therapeutic interventions. We will then use the model to test whether target dysregulated respiratory CD8+ T cell responses could ameliorate chronic lung sequelae post-acute COVID-19. We will employ system biology tools to The successful completion of the study will generate unprecedented insights on clinical, viral, and immune traits of pulmonary sequelae, and will identify key causal immune mechanisms and therapeutic targets against chronic lung diseases post-acute COVID-19.

项目概要除了 SARS-CoV-2 引起的急性疾病外，现在清楚的是，很大一部分患者 COVID-19 后出现长期病症，包括全身和呼吸道症状。鉴于 SARS-CoV-2 感染在全球范围内灾难性传播，许多人从急性感染中恢复过来 COVID-19 会导致肺功能永久性损伤，从而导致劳力性呼吸困难、疲劳（由于慢性缺氧）和其他限制。随着疫情的持续发展，这个数字还会变得更大进步。因此，迫切需要了解其发展的机制。 COVID-19 的慢性呼吸道后遗症的发展预防和治疗干预措施。在此应用中，我们的目标是揭示慢性疾病的驱动机制并确定潜在的治疗靶点 COVID-19 后的肺部后遗症。为了实现这一目标，我们提出了本研究的两个具体目标（SA）。 SA 1. 解读急性 COVID-19 后慢性肺部后遗症的细胞和分子特征。我们将注册一群 COVID-19 康复者在经历过严重的疾病后预计会出现慢性肺部后遗症急性疾病和从之前的轻度或无症状中完全康复的对照人群 2019冠状病毒病感染。我们将进行全面的临床检查并辅以定量胸部检查 CT 成像和肺功能测试以确定临床和病理生理特征两个人口。我们将收集纵向血液和支气管肺泡灌洗液（BAL）以获得免疫， COVID-19 康复者和对照者的分子和病毒特征。这种独特的方法整合了控制或新冠病毒的全身和呼吸道临床、病理生理学、细胞、分子和病毒特征 19 名康复者对于未来可药物靶点的发现将非常引人注目。 SA2。建模和验证动物模型中急性 COVID-19 后慢性肺部后遗症的目标。我们将建立一个小鼠模型急性 COVID-19 后慢性肺部后遗症的研究。我们将表征系统和呼吸宿主细胞和模型中的分子反应。整合小鼠和人类数据验证机制联系并发现治疗干预的新见解和/或目标。我们将然后使用该模型来测试目标失调的呼吸 CD8+ T 细胞反应是否可以改善急性 COVID-19 后的慢性肺部后遗症。我们将利用系统生物学工具来该研究的成功完成将对临床、病毒和免疫特征产生前所未有的见解肺部后遗症的研究，并将确定针对慢性病的关键因果免疫机制和治疗靶点急性 COVID-19 后的肺部疾病。