Ace2 in the healthy and inflamed taste system

项目摘要/摘要 味觉缺陷在感染SARS-CoV-2的人中很普遍，这种病毒导致了 全球新冠肺炎大流行。味觉丧失会对营养和质量产生负面影响。 在一些患者中，这种缺陷是长期存在的。味觉减退的生物学基础 SARS-CoV-2病毒在很大程度上是未知的。我们的初步结果表明，ACE2受体 和TMPRSS2共同介导SARS-CoV-2宿主细胞进入在味蕾中表达 这表明它们有可能被病毒感染。味觉细胞ACE2的功能，也是 调节液体平衡的肾素-血管紧张素系统尚不清楚。我们已经开发出 三个新的遗传小鼠品系克服了现有小鼠的局限性 模特们。在目标1中，我们映射ACE2报告表达来确定哪个味觉感受器细胞 人群和途径是SARS-CoV-2的潜在目标。在目标2中，我们测试如何使用语言 上皮特异性ACE2在味觉感受器细胞动力学和神经生理学中的作用 在基线和炎症条件下的味觉反应。我们还将测试如何品尝 人SARS-CoV-2刺突蛋白对人源化ACE2基因敲入功能的影响 老鼠。我们的假设预测味蕾是SARS-CoV-2的目标，味觉ACE2 有助于味觉功能并在炎症期间起到保护作用，而SARS-CoV-2尖峰 蛋白质会加剧味蕾的损伤，并抑制神经味觉反应 炎症状态。此R21试探性/开发性拨款申请解决了 迫切需要对人类味觉失调的潜在机制有基本的了解 还有新冠肺炎。

PROJECT SUMMARY / ABSTRACT Taste deficits are prevalent in people infected with SARS-CoV-2, the virus responsible for the global COVID-19 pandemic. The loss of taste sensation negatively affects nutrition and quality of life and in some patients this deficit is long-lasting. The biological basis for taste loss due to SARS-CoV-2 is largely unknown. Our preliminary results demonstrate that the ACE2 receptor and TMPRSS2 which together mediate SARS-CoV-2 host cell entry are expressed in taste buds indicating their potential for viral infection. The function of taste cell ACE2, also a member of the renin-angiotensin system that regulates fluid balance, is unknown. We have developed three novel genetic mouse strains to overcome the limitations of currently available mouse models. In aim 1 we map ACE2 reporter expression to determine which taste receptor cell populations and pathways are potential targets of SARS-CoV-2. In aim 2 we test how lingual epithelium-specific ACE2 contributes to taste receptor cell dynamics and neurophysiological taste responses under baseline and inflammatory conditions. We will also test how taste function is affected by human SARS-CoV-2 spike protein in a humanized ACE2 knock-in mouse. Our hypothesis predicts that taste buds are SARS-CoV-2 targets, that taste ACE2 contributes to taste function and is protective during inflammation, and that SARS-CoV-2 spike protein will exacerbate damage in taste buds and depress neural taste responses under inflammatory conditions. This R21 Exploratory / Developmental grant application addresses the urgent need for fundamental insights to mechanisms underlying taste dysregulation in people with COVID-19.