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

基本信息

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
项目类别：
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

项目摘要

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：这是母版 R01“理解分子遗传机制”的行政补充哮喘风险位点：IL33、IL1RL1 和 GSDMB”，重点了解遗传多态性如何影响改变 IL-1 家族细胞因子 IL-33 的上皮分泌本补充题为“泰坦之战：了解气道上皮干扰素和 IL-1 对 SARS-CoV-2 感染的反应，” 我们的假设是 SAR-CoV-2 病毒的一个关键毒力因素， E 蛋白以 Gasdermin 和 Caspase 依赖性方式触发上皮细胞分泌 IL-1B。 IL-1 分泌以自分泌方式发挥作用，抑制关键的干扰素反应，而干扰素反应是该建议允许我们的实验室将病毒限制在上呼吸道并防止下呼吸道感染。使用我们作为父母资助的一部分产生的基因改造细胞系来快速研究气道上皮对 SARS-CoV-2 感染的干扰素和 IL-1 反应及商业测试该提案旨在通过阻断半胱天冬酶或 IL-1 信号传导来快速抑制病毒复制。转化我们目前对气道上皮细胞生物学的理解，以满足治疗的迫切需求对抗 SARS-CoV-2 病毒，该病毒目前已感染全球超过 100 万人并导致死亡不到 4 个月的时间就增加了 60,000 多个。