Molecular understanding of the GSDMB-regulated innate immune response

GSDMB 调节的先天免疫反应的分子理解

• 批准号: 10583794
• 负责人: Anny Xiaobo Zhou
• 金额: $ 65.34万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583794
• 关键词: 17q; 17q21; 2019-nCoV; Acute; Affect; Age; Air; Antiviral Response; Asthma; Binding; Biochemical; Biological; Cell model; Cells; Child; Childhood Asthma; Chromosomes; DNA; Data; Development; Double-Stranded RNA; Drug Targeting; Elderly; Environmental Risk Factor; Epithelial Cells; Family member; Genes; Genetic; Genetic Transcription; Genotype; Goals; Guide RNA; Health; Homologous Gene; Human; Hyperplasia; Immune response; In Vitro; Individual; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Activation; Interferons; Invaded; Knock-out; Life; Liquid substance; Measures; Mediating; Modeling; Molecular; Mucous body substance; Mus; Neonatal; Nucleic Acids; Persons; Poly I-C; Precision therapeutics; Predisposition; Production; Public Health; RNA; RNA Virus Infections; RNA Viruses; Respiratory Disease; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Rhinovirus infection; Risk; Role; School-Age Population; Series; Severities; Signal Pathway; Signal Transduction; Susceptibility Gene; Testing; Time; Transgenic Mice; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; airway epithelium; airway hyperresponsiveness; airway inflammation; analog; asthma exacerbation; asthmatic; asthmatic patient; bronchial epithelium; chemokine; gene environment interaction; genome wide association study; genome-wide analysis; in vivo; inducible gene expression; infancy; inhibitor; insight; mouse model; mucus hypersecretion; neonatal mice; novel; overexpression; pandemic disease; prevent; promoter; respiratory; respiratory infection virus; respiratory virus; response; risk variant; sensor; social; unpublished works; viral RNA

Project Summary Respiratory virus infection, an increasing health and social burden alone, also increases risk for development and exacerbation of other respiratory diseases, including asthma that affects 17 million U.S. people. Viral infection triggers innate immune response, an important defensive mechanism through activation of the interferon signaling: robust induction of antiviral proteins including interferons (IFNs) and interferon-stimulated genes (ISGs) through the recognition of viral nucleic acid and activation of subsequent signal cascades. Specifically, intracellular viral RNA is sensed and recognized by RNA sensors, which subsequently activates series of signaling cascade to induce the production of IFNs. Secreted IFNs, in turn, activates the transcription of hundreds of ISGs to amplify innate immune response, a double-edged sword, both constraining viral replication and without proper control, leading to exuberant inflammatory response that damages airway epithelium during asthma exacerbation caused by viral infection. Furthermore, such virus-induced asthmatic exacerbation has a strong genetic basis. Chromosome 17q21 Gasdermin B (GSDMB) region has been significantly associated with susceptibility and severity of childhood asthma, primarily in children who had prior respiratory virus infection. However, the mechanism by which how viral infection determines the asthmatic susceptibility among individuals with various genetic background is incompletely understood, which is the major focus of the proposal. Notably, the genotype of 17q21 asthma risk allele is associated with increased expression of GSDMB in human airway epithelial cells. Our unpublished work has demonstrated that GSDMB is not only sufficient but also required to promote IFNs signaling and induce expression of ISGs in human airway epithelial cells treated with RNA viruses or their analogue: poly (I:C). We now propose to characterize the biological and molecular mechanism by which GSDMB determines the risk for asthma following RNA virus infection. We have proposed a series of integrative and complementary in vitro, ex vivo and in vivo approaches to 1) dissect the molecular mechanisms by which GSDMB promotes IFNs signaling (Aim 1); 2) establish the Rhinovirus infection cellular model with prolonged inflammatory response induced by GSDMB in human bronchial epithelial cells with opposing genotypes of GSDMB (Aim 2); 3) in vivo consequence of prolonged and repetitive respiratory virus infection in mice with conditional and inducible expression of human GSDMB in airway epithelial cells (Aim 3). Our deep mechanistic understanding of such gene by environment interaction will illuminate novel treatment and perturbation strategy to prevent severe asthma exacerbation in susceptible subjects.

项目摘要 呼吸道病毒感染，仅健康和社会负担增加，也会增加发展的风险 加剧其他呼吸道疾病，包括影响1700万美国人的哮喘。病毒性的 感染触发先天免疫反应，这是一种通过激活的重要防御机制 干扰素信号传导：抗病毒蛋白（包括干扰素（IFN）和干扰素刺激）的耐用诱导 通过识别病毒核酸的基因（ISG）和随后的信号级联反应的激活。 具体而言，细胞内病毒RNA被RNA传感器感测并识别，随后激活 一系列信号级联反应以诱导IFN的产生。分泌的IFN又激活了转录 数百个ISGs以扩增先天免疫反应，这是一把双刃剑，都限制了病毒 复制并且没有适当的控制，导致炎症反应损害气道 由病毒感染引起的哮喘加剧期间上皮。此外，这种病毒引起的哮喘 恶化具有强大的遗传基础。染色体17q21 Gasdermin B（GSDMB）区域已 与儿童哮喘的易感性和严重程度显着相关，主要是在先前的儿童中 呼吸道病毒感染。但是，病毒感染如何决定哮喘的机制 具有各种遗传背景的个体的敏感性尚不完全理解，这就是 提案的主要重点。值得注意的是，17q21哮喘风险等位基因的基因型与增加有关 GSDMB在人气道上皮细胞中的表达。我们未发表的工作表明GSDMB 不仅足够，而且还需要促进IFN信号传导和诱导人类的表达 用RNA病毒或其类似物处理的气道上皮细胞：poly（i：c）。我们现在建议描述 GSDMB确定RNA病毒后哮喘风险的生物学和分子机制 感染。我们提出了一系列体外，体内和体内方法的综合和互补的方法 到1）剖析GSDMB促进IFNS信号传导的分子机制（AIM 1）； 2）建立 鼻病毒感染细胞模型具有长期的炎症反应，由GSDMB诱导 带有GSDMB基因型的支气管上皮细胞（AIM 2）； 3）延长的体内结果 人类GSDMB在小鼠中的重复呼吸道病毒感染 气道上皮细胞（AIM 3）。我们通过环境相互作用对这种基因的深刻理解 将阐明新颖的治疗和扰动策略，以防止易感的严重哮喘恶化 主题。