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Balancing epithelial cell resistance and resilience to respiratory viral infections

平衡上皮细胞抵抗力和对呼吸道病毒感染的抵抗力

基本信息

批准号：
10851237
负责人：
Jose Manuel Ordovas-Montanes
金额：
$ 4.7万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10851237
关键词：
2019-nCoV Agonist Air Automobile Driving B lymphocyte-induced maturation protein 1 B-Lymphocytes Basal Cell COVID-19 COVID-19 patient CRISPR-mediated transcriptional activation Cell Lineage Cells Cellular Metabolic Process Code Complement Complement Factor B Computer Analysis Data Disease Epithelial Cells Epithelium Equilibrium Event FOXO3A gene Functional disorder Future Generations Genes Genetic Transcription Goals Goblet Cells Grant Human Immune Immune response Immunosuppression Individual Infection Influenza Interferons Knowledge Liquid substance Literature Lower respiratory tract structure Modeling Mus Nasal Epithelium Neoplasm Metastasis Oxidative Stress Ozone PRDM1 gene Pathway interactions Patients Predictive Factor Prevalence RNA RNA Virus Infections Reporting Research Resistance Rhinovirus Role SARS-CoV-2 infection Secretory Cell Severity of illness Specific qualifier value Structure of mucous membrane of nose System Tetracyclines Therapeutic Transfection Upper respiratory tract Viral Viral Respiratory Tract Infection Virus Virus Diseases Work adeno-associated viral vector airway epithelium antiviral immunity cell type gene regulatory network human data in vivo influenza infection interest mouse model nasopharyngeal swab pandemic disease programs public health relevance resilience response severe COVID-19 single-cell RNA sequencing tissue tropism transcription factor transcriptome sequencing tumor tumorigenesis vector viral pandemic

项目摘要

SUPPLEMENT PROJECT SUMMARY Single-cell studies of the nasal mucosa of COVID-19 and influenza patients have helped to identify epithelial cell subsets and states that are associated with disease severity. Our project’s goal is to determine the roles of specific transcription factors in specifying the fates and functions of discrete nasal epithelial cell subsets. We have prioritized these epithelial subsets, which appear to emerge from the goblet cell lineage, based on our preliminary data that highlight how closely-related goblet cell subsets are significantly enriched or depleted as targets of viral infection. Our central hypothesis is that the combined activation of two transcription factors will specify goblet cells that are uniquely-protected from RNA viral infection. Aim 1 will determine the downstream targets and gene regulatory networks induced by these transcriptional regulators, and Aim 2 will investigate the role of these transcription factors in regulating antiviral immunity in goblet cells. Identifying the transcriptional regulators of these goblet cells will allow for the generation of better ex vivo models to study their function, and to potentially rebalance epithelial cells in vivo to better-protect the nasal mucosa from viral infection.

补充项目总结新冠肺炎和流感患者鼻黏膜的单细胞研究有助于识别上皮细胞与疾病严重程度相关的细胞亚群和状态。我们项目的目标是确定特定转录因子在确定离散鼻腔上皮细胞亚群命运和功能中的作用。我们根据我们的研究，确定了这些上皮亚群的优先顺序，这些亚群似乎是从杯状细胞谱系中产生的初步数据突出了密切相关的杯状细胞亚群是如何显著富含或消耗为病毒感染的目标。我们的中心假设是，两个转录因子的联合激活将指定独特保护不受RNA病毒感染的杯状细胞。目标一号将决定下游由这些转录调控因子诱导的靶点和基因调控网络，Aim 2将研究这些转录因子在调节杯状细胞抗病毒免疫中的作用。鉴定转录本这些杯状细胞的调节将允许产生更好的体外模型来研究它们的功能，以及潜在地重新平衡体内的上皮细胞，以更好地保护鼻黏膜免受病毒感染。