Function interactions between mitogen-activated protein kinases (MAPKs) and SARS-CoV-2

丝裂原激活蛋白激酶 (MAPK) 与 SARS-CoV-2 之间的功能相互作用

基本信息

批准号：
10659904
负责人：
Jeffrey R Johnson
金额：
$ 88.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2023-03-13 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659904
关键词：
2019-nCoV Acute Respiratory Distress Syndrome Affect Animals Antiviral Therapy Area Bioinformatics COVID-19 pandemic COVID-19 treatment CRISPR/Cas technology Cells Cessation of life Chemicals Combined Modality Therapy Dependence Disease Disease Outcome Drug Targeting Effectiveness Family Generations Genetic Genetic Screening Genome Human Immune Immune response Infection Infiltration Inflammation Inflammatory Interleukin-6 Lung Measures Mediating Methods Mitogen-Activated Protein Kinase Inhibitor Mitogen-Activated Protein Kinases Modeling Modification Molecular Multiple Organ Failure Mutate Mutation Nucleoproteins Organoids Pathogenicity Pathway interactions Paxlovid Phenotype Phosphorylation Site Phosphotransferases Play Predisposition Production Protease Inhibitor Proteins Proteome Proteomics Recombinants Regulation Research Respiratory Failure Role SARS-CoV-2 infection SARS-CoV-2 inhibitor Signal Transduction Small Interfering RNA Technology Testing Vaccines Viral Viral Proteins Virus Replication Work base editing cytokine human stem cells in vivo interdisciplinary approach mouse model new therapeutic target nucleoside analog p38 Mitogen Activated Protein Kinase phosphoproteomics prevent recombinant virus remdesivir respiratory infection virus response severe COVID-19 small molecule stem cells tool

项目摘要

PROJECT SUMMARY SARS-CoV-2, the causative agent of the COVID-19 pandemic, modifies the cells that it infects in profound ways. One such modification is the activation of host cellular mitogen-activated protein kinase (MAPK) pathways, which contribute to severe inflammation that is a hallmark of severe COVID-19 disease. Inhibition of one MAPK pathway, the p38/MAPK pathway, reduces SARS-CoV-2 replication by an undefined mechanism. This proposal aims to measure the impact of human MAPK pathways on SARS-CoV-2 infection using a multidisciplinary approach that combines state-of-the-art proteomics technologies, medium-throughput genetic screening, and in vivo and ex vivo models of SARS-CoV-2 infection. These findings will inform the potential application of MAPK inhibitors for COVID-19 treatment and may identify alternative targets within the MAPK families. MAPK pathways play critical roles in many disease states, and this work will inform research in these areas by providing molecular mechanisms for MAPK regulation and providing tools for the unbiased discovery of MAPK substrates and regulators.

项目概要 SARS-CoV-2 是 COVID-19 大流行的病原体，它会深刻地改变其感染的细胞。其中一种修饰是宿主细胞丝裂原激活蛋白激酶 (MAPK) 途径的激活，该途径导致严重炎症，这是严重 COVID-19 疾病的标志。抑制一种 MAPK p38/MAPK 通路通过一种未定义的机制减少 SARS-CoV-2 的复制。这个提议旨在利用多学科方法衡量人类 MAPK 通路对 SARS-CoV-2 感染的影响该方法结合了最先进的蛋白质组学技术、中等通量遗传筛选和 SARS-CoV-2 感染的体内和离体模型。这些发现将为 MAPK 的潜在应用提供信息 COVID-19 治疗的抑制剂，并可能确定 MAPK 家族中的替代靶点。 MAPK通路在许多疾病状态中发挥着关键作用，这项工作将为这些领域的研究提供分子信息 MAPK 调节机制并为公正地发现 MAPK 底物提供工具监管机构。