Role and Mitigation of Inflammasomes and Inflammation During COVID-19

COVID-19 期间炎症小体和炎症的作用和缓解

基本信息

批准号：
10521963
负责人：
Beverly H Koller
金额：
$ 57.14万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521963
关键词：
2019-nCoV Acute Respiratory Distress Syndrome Agonist Alveolar Apoptosis Binding Biological Markers CASP1 gene COVID-19 COVID-19 pandemic COVID-19 patient COVID-19/ARDS Cell Death Cells Cessation of life Clinical Trials Coculture Techniques Complex Conflict (Psychology)Consequentialism Dangerousness Data Deterioration Epithelial Cells Genes Genetic Transcription Human Immune Inflammasome Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-1 Receptors Interleukin-18 Interleukin-6 Irrigation Lead Leukocytes Meta-Analysis Modification Molecular Mus Myeloid Cells Outcome Pathway interactions Patients Pattern Peripheral Blood Mononuclear Cell Phase Potassium Process Production Proteins Randomized Clinical Trials Reporting Role SARS-CoV-2 infection SARS-CoV-2 pathogenesis Signal Transduction Stromal Cells Structure Structure of parenchyma of lung TNF gene Testing Translations Urokinase Plasminogen Activator Receptor Virus airway epithelium anakinra antagonist cell injury chemokine cytokine cytokine release syndrome design in vivo inhibitor interleukin-1beta-converting enzyme inhibitor marenostrin member mortality pathogen receptor response sensor severe COVID-19 single-cell RNA sequencing standard care success therapeutic target therapeutically effective thrombotic

项目摘要

Project Abstract The COVID-19 pandemic caused by SARS-CoV-2 has resulted in swift and catastrophic losses of human lives globally. Acute respiratory distress syndrome (ARDS) is one of the most detrimental outcomes of COVID-19 infection that can lead to the rapid deterioration and death of patients. ARDS is primarily caused by the cytokine storm which unleashes a plethora of inflammatory cytokines during the late stages of COVID-19. The master cytokines that are thought to be responsible for much of the damage are interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor (TNF). Currently two clinical trials have shown the efficacy of IL-1 inhibitor in COVID- 19 patients. However, in many cases, the mechanism and impact of these cytokines during SARS-CoV-2 infection are poorly understood. An in-depth mechanistic understanding of cytokine induction is important because this understanding will significantly impact the design and success of ARDS treatment. This application focuses on the role and mitigation of the inflammasome complex which leads to the proinflammatory cytokine, IL-1β, in ARDS. The inflammasome is a protein supramolecular structure that leads to caspase 1 activation, which then cleaves pro-IL-1β and pro-IL-18 to mature IL-1β and IL-18. In addition to the release of IL-1β and IL- 18, caspase 1 cleaves gasdermin D to cause inflammatory pyroptotic cell death, thus leading to a cascade of cell death and inflammation. The inflammasome is comprised of a receptor or sensor, with the most prominent ones represented by NLRP1, NLRP3, NLRP6, NLRC4 and AIM2. It also includes an adaptor molecule ASC (apoptosis-associated speck-like protein containing a CARD), and the effector caspase-1. Each receptor or sensor can be activated by specific pathogen products called PAMPs or cell damage associated molecules called DAMPs. Single cell RNAseq data from COVID-19 patients show dramatic increases of inflammasome sensors in the bronchial alveolar lavage of severe COVID-19 patients. In addition, we find a bidirectional feed- forward loop of inflammasome activation and inflammatory cytokine induction involving myeloid cells and airway stromal cells. This proposal will test the hypothesis that this two way amplification loop is important in COVID- 19.

项目摘要由 SARS-CoV-2 引起的 COVID-19 大流行已导致迅速而灾难性的人员伤亡在全球范围内，急性呼吸窘迫综合征 (ARDS) 是 COVID-19 最令人痛苦的后果之一。导致ARDS患者病情迅速恶化和死亡的感染主要是由细胞因子引起的。在 COVID-19 的晚期，风暴会释放出大量的炎症细胞因子。人们认为造成大部分损伤的细胞因子是白细胞介素 1 (IL-1)、白细胞介素 6 (IL-6) 目前两项临床试验已显示IL-1抑制剂在新冠肺炎中的疗效。 19 名患者。然而，在许多情况下，这些细胞因子在 SARS-CoV-2 期间的机制和影响。对细胞因子诱导的深入机制了解很重要。因为这种理解将显着影响 ARDS 治疗的设计和成功。重点关注导致促炎细胞因子的炎性体复合物的作用和缓解， IL-1β，在 ARDS 中，炎症小体是一种蛋白质超分子结构，可导致 caspase 1 激活，然后，除了释放 IL-1β 和 IL-1 之外，还将 pro-IL-1β 和 pro-IL-18 裂解为成熟的 IL-1β 和 IL-18。 18、caspase 1 裂解gasdermin D 导致炎性焦亡细胞死亡，从而导致级联反应细胞死亡和炎症。炎症小体由受体或传感器组成，其中最突出的是。其还包括以NLRP1、NLRP3、NLRP6、NLRC4和AIM2为代表的接头分子ASC。（含有 CARD 的凋亡相关斑点样蛋白）和效应器 caspase-1 各受体或。传感器可以被称为 PAMP 的特定病原体产物或细胞损伤相关分子激活来自 COVID-19 患者的称为 DAMP 的单细胞 RNAseq 数据显示炎症小体急剧增加。此外，我们还发现了一种双向馈送传感器用于重症 COVID-19 患者的支气管肺泡灌洗。涉及骨髓细胞和气道的炎症小体激活和炎症细胞因子诱导的前向循环该提案将检验这种双向扩增循环在新冠病毒中很重要的假设。 19.