Understanding the Molecular Genetic Mechanisms of Asthma Risk Loci: IL33, IL1RL1, and GSDMB - COVID 19 Supplement

了解哮喘风险位点的分子遗传机制：IL33、IL1RL1 和 GSDMB - COVID 19 补充资料

• 批准号: 10265648
• 负责人: Erin D. Gordon
• 金额: $ 15.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265648
• 关键词: 17q21; Address; Airway Disease; Alternative Splicing; Asthma; Basophils; Binding; Biological; Biology; Blood; CRISPR/Cas technology; Cadaver; Calcium; Caspase; Cell Nucleus; Cell membrane; Cell physiology; Cells; Cellular biology; Cues; Cytoplasm; DNA; DNA mapping; Data; Development; Disease; Epithelial Cells; Family; Gene Expression; Gene Order; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Variation; Genomics; Goals; Heritability; Histones; Human; Immune response; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 beta; Label; Length; Link; Lung; Lymphoid; Maps; Measures; Membrane; Methods; Molecular; Molecular Disease; Molecular Genetics; Mus; Nuclear; Pathologic; Pathology; Pathway interactions; Patients; Peptide Signal Sequences; Protein Overexpression; Proteins; Public Health; Quantitative Trait Loci; RNA Splicing; Research Personnel; Risk; Role; Signal Transduction; Surface; Target Populations; Testing; Th2 Cells; Therapeutic Intervention; Transcript; Variant; airway epithelium; asthmatic; asthmatic airway; causal variant; cohort; cytokine; extracellular; gene function; genetic epidemiology; genetic variant; genome wide association study; genomic locus; human subject; in vivo; inhibitor/antagonist; knock-down; mast cell; mouse model; novel; novel therapeutics; receptor; receptor binding; response; risk variant

PROJECT SUMMARY: This is an administrative supplement to the parent R01 “Understanding the Molecular Genetic Mechanisms of Asthma Risk Loci: IL33, IL1RL1, and GSDMB,” which focuses on understanding how genetic polymorphisms alter epithelial secretion of the IL-1 family cytokine, IL-33. This supplement entitled “Clash of Titans: Understanding the Airway Epithelial Interferon and IL-1 Response to SARS-CoV-2 Infection,” addresses a critical need during a global pandemic. Our hypothesis is that a key virulence factor in the SAR-CoV-2 virus, the E protein, triggers IL-1B secretion from epithelial cells in a gasdermin and caspase dependent manner. That IL-1 secretion acts in an autocrine fashion, to inhibit critical interferon responses that are required to constrain the virus to the upper airway and prevent lower airway infection. The proposal allows our laboratory to use genetically altered cell lines that we generated as part of the parent grant to quickly study the balance of interferon and IL-1 responses of the airway epithelium to SARS-CoV-2 infection and test commercially available drugs that block caspases or IL-1 signaling to inhibit viral replication. This proposal seeks to rapidly translate our current understanding of airway epithelial cell biology to address a critical need for therapeutics against the SARS-CoV-2 virus which has currently infected more than a million people worldwide and killed over 60,000 in less than 4 months.

项目概要： 这是对父R 01“了解遗传病的分子遗传机制”的管理补充。 哮喘风险基因座：IL 33，IL 1 RL 1和GSDMB，”重点是了解遗传多态性如何 改变IL-1家族细胞因子IL-33的上皮分泌。这一补充题为“冲突的泰坦： 了解呼吸道上皮干扰素和IL-1对SARS-CoV-2感染的反应， 在全球大流行期间的关键需求。我们的假设是，SAR-CoV-2病毒的一个关键毒力因子， E蛋白以gasdermin和半胱天冬酶依赖性方式触发上皮细胞分泌IL-1B。 IL-1的分泌以自分泌的方式起作用，以抑制关键的干扰素反应， 将病毒限制在上呼吸道，防止下呼吸道感染。该提案允许我们的实验室 使用我们作为父母资助的一部分产生的基因改变的细胞系， 气道上皮细胞对SARS-CoV-2感染的干扰素和IL-1反应和商业测试 阻断半胱天冬酶或IL-1信号传导以抑制病毒复制的药物。该提案旨在迅速 将我们目前对气道上皮细胞生物学的理解转化为治疗的关键需求， 针对SARS-CoV-2病毒，该病毒目前已感染全球100多万人， 在不到4个月的时间里超过6万人。