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

• 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
• 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

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.

验证项目摘要 对COVID-19和流感患者鼻粘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 特异性转录因子在指定离散鼻上皮细胞亚群的命运和功能。我们 根据我们的研究，我们已经优先考虑了这些上皮亚群，它们似乎来自杯状细胞谱系。 初步数据突出了密切相关的杯状细胞亚群如何显著富集或耗尽， 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 指定杯状细胞，其被严格保护以免受RNA病毒感染。目标1将决定下游 目标和基因调控网络诱导这些转录调控因子，目标2将探讨 这些转录因子在调节杯状细胞抗病毒免疫中的作用。识别转录 这些杯状细胞的调节剂将允许产生更好的离体模型来研究它们的功能， 以潜在地在体内重新平衡上皮细胞，从而更好地保护鼻粘膜免受病毒感染。