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

项目总结： 这是对亲本R01的行政补充。 哮喘风险基因：IL33、IL1RL1和GSDMB。 改变上皮细胞分泌IL-1家族细胞因子IL-33。这份名为《泰坦之战》的副刊： 了解呼吸道上皮细胞干扰素和IL-1对SARS-CoV-2感染的反应 在全球大流行期间的迫切需要。我们的假设是，SARS-CoV-2病毒中的一个关键毒力因素， E蛋白以Gasdermin和caspase依赖的方式刺激上皮细胞分泌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，而干扰素是 将病毒限制在上呼吸道，防止下呼吸道感染。这项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转基因细胞系来快速研究 呼吸道上皮细胞对SARS-CoV-2感染的干扰素和IL-1反应及商业化检测 阻断半胱氨酸酶或IL-1信号以抑制病毒复制的现有药物。这项提议寻求迅速 翻译我们目前对呼吸道上皮细胞生物学的理解，以满足治疗的迫切需要 对抗SARS-CoV-2病毒，该病毒目前已在全球感染并导致100多万人死亡 在不到4个月的时间里超过了6万人。

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.