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Ace2 in the healthy and inflamed taste system

Ace2 在健康和炎症味觉系统中的作用

基本信息

批准号：
10570979
负责人：
Lin Gan
金额：
$ 19.25万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570979
关键词：
2019-nCoV ACE2 Address Affect Ageusia Aldosterone Angiotensin II Animal Model Anosmia Anterior Anti-Inflammatory Agents Antibodies Applications Grants Automobile Driving Behavior Binding Biological Blood Pressure Blood Vessels COVID-19 COVID-19 pandemic COVID-19 patient Cathepsins Cell Count Cells Chimeric Proteins Coughing Development Disease Down-Regulation Epidemic Epithelium Esthesia Exploratory/Developmental Grant Fatigue Fever Fluid Balance Functional disorder Future Genetic Hormones Human Immune response Inflammation Inflammatory Knock-in Knock-in Mouse Knock-out Knockout Mice Knowledge Lipopolysaccharides LoxP-flanked allele Maps Measures Mediating Modeling Mouse Strains Mus Nerve Neural Pathways Neuroglia Neurons Organ Pathogenesis Pathway interactions Patients Peptide Hydrolases Peripheral Persons Population Proteins Quality of life Receptor Cell Renin-Angiotensin System Reporter Research Respiratory distress Role SARS coronavirus SARS-CoV-2 infection SARS-CoV-2 spike protein Severe Acute Respiratory Syndrome Smell Perception Stimulus Structure TMPRSS2 gene Tactile Taste Buds Taste Perception Testing Tropism Viral Virus Virus Diseases afferent nerve behavioral response cell type chorda tympani common symptom insight lung injury member mouse model negative affect nerve injury neural neurophysiology novel nutrition patient subsets receptor receptor binding response taste system

项目摘要

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.

项目概要/摘要感染 SARS-CoV-2 的人普遍存在味觉缺陷，这种病毒是导致全球 COVID-19 大流行。味觉丧失会对营养和质量产生负面影响生命的丧失，并且在某些患者中，这种缺陷是长期持续的。味觉丧失的生物学基础 SARS-CoV-2 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 进入宿主细胞，并在味蕾中表达表明它们具有病毒感染的潜力。味觉细胞 ACE2 的功能，也是调节体液平衡的肾素-血管紧张素系统尚不清楚。我们开发了三种新型基因小鼠品系克服了现有小鼠的局限性模型。在目标 1 中，我们绘制了 ACE2 报告基因表达图，以确定哪个味觉受体细胞人群和途径是 SARS-CoV-2 的潜在目标。在目标 2 中，我们测试语言能力上皮特异性 ACE2 有助于味觉受体细胞动力学和神经生理学基线和炎症条件下的味觉反应。我们也会测试一下味道如何人源化 ACE2 敲入中的功能受到人类 SARS-CoV-2 刺突蛋白的影响老鼠。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具有保护作用，并且 SARS-CoV-2 会激增蛋白质会加剧味蕾损伤并抑制神经味觉反应炎症状况。此 R21 探索性/开发拨款申请解决了迫切需要对人类味觉失调的机制有基本的了解与新冠肺炎 (COVID-19) 相关。