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Influence of NSAIDs and AERD on the expression and function of ACE2 - implications for SARS-CoV2 severity

Influence of NSAIDs and AERD on the expression and function of ACE2 - implications for SARS-CoV2 severity
NSAID 和 AERD 对 ACE2 表达和功能的影响 - 对 SARS-CoV2 严重程度的影响
批准号:
10197400
负责人:
Joshua A Boyce
金额:
$11.42万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-07-24 至 2022-06-30

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中文摘要
翻译
项目总结/摘要 SARS-CoV 2需要血管紧张素转换酶2(ACE 2)与宿主鼻上皮细胞结合。 然而,当SARS-CoV与ACE 2结合时,内化导致ACE 2活性降低。ACE 2可以 产生生物活性肽(Ang(1-9)和Ang(1-7)),其可保护免受严重的COVID-1 - 9- 导致肺损伤。因此,尽管鼻上皮中ACE 2的表达是病毒感染鼻粘膜所需的进入点, 感染后,持续高水平的ACE 2活性可能矛盾地提供一旦患者感染的益处。的 调节ACE 2表达和活性的宿主因子尚不完全清楚,并且缺少调节ACE 2表达和活性所需的片段。 扩大我们对这种疾病发病机制的了解。 2020年3月,法国卫生部长表示,NSAID的使用可能与更严重的 新冠肺炎患者的疾病表现。现在有一个绝望的尝试,以了解是否 NSAID的使用只是与呼吸系统结果恶化相关,或实际上是呼吸系统结果恶化的原因。发烧和 肌痛与COVID-19相关,并且两者通常都假定用NSAID治疗,因此必须 我们了解了非甾体抗炎药在这种疾病中的免疫影响。 人们还相当担心可能出现更严重的COVID-19相关呼吸道疾病, 2型炎症患者的疾病,以及阿司匹林加重的呼吸道疾病患者的亚组, 疾病(AERD)在鼻窦的解剖区域有严重的上呼吸道炎症 其中ACE 2表达最高。目前尚不清楚慢性病的存在是如何造成的。 2型呼吸道炎症会影响呼吸道或血液中的ACE 2水平。 我们收集了鼻上皮细胞(用于ACE 2表达的mRNA评估), 以及血清和血浆(用于如上所述的血管紧张素衍生肽的ELISA测量), 已存入银行并可立即进行分析。有了这些,我们的目标是阐明两个问题, 评估和治疗COVID-19患者: 1)使用NSAID是否会增加COVID-19严重并发症的风险? 2)患有哮喘和2型呼吸道炎症的患者是否会增加严重呼吸道疾病的风险? COVID-19的并发症? 这些目标的完成将使我们能够就NSAID在以下人群中的安全性提出建议: 2019冠状病毒病。许多患者目前选择停止他们的定期处方阿司匹林和非甾体抗炎药, 恐惧,我们怀疑这是毫无根据的。我们还将进一步了解重症2型患者是否 呼吸道炎症有不同的鼻ACE 2表达和血管紧张素肽水平,相比之下, 健康对照,这表明这些患者患严重COVID-19的风险不同。
英文摘要
PROJECT SUMMARY/ABSTRACT SARS-CoV2 requires angiotensin-converting enzyme 2 (ACE2) to bind to host nasal epithelial cells. However, upon binding of SARS-CoV to ACE2, internalization leads to decreased ACE2 activity. ACE2 can generate biologically active peptides (Ang(1-9) and Ang(1-7)) which are protective against severe COVID-19- induced lung injury. Therefore, although ACE2 expression in the nasal epithelium is a required entry point for viral infection, continued high levels of ACE2 activity may paradoxically provide benefit once the patient is infected. The host factors that regulate ACE2 expression and activity are not fully known and are missing pieces required to expand our understanding of the pathogenesis of this disease. In March 2020 a French health minister suggested that NSAID use might be associated with more severe disease presentation in patients with COVID-19. There is now a desperate attempt to understand whether NSAID use is simply correlated with, or actually causative of, worsened respiratory outcomes. As fever and myalgias are associated with COVID-19, and both are often treated presumptively with NSAIDs, it is imperative that we understand the immunological influence of NSAIDs in this disease. There is also considerable concern regarding the potential for more severe COVID-19-related respiratory disease in patients with Type 2 inflammation, and the subset of patients with aspirin-exacerbated respiratory disease (AERD) have severe upper respiratory inflammation in exactly the anatomic areas of the sinuses where ACE2 expression has been found to be the highest. It is not yet known how the presence of chronic Type 2-driven respiratory inflammation affects ACE2 levels in the respiratory tract or the blood. We have collected nasal epithelial cells (for mRNA assessment of ACE2 expression), and both nasal fluid and serum and plasma (for ELISA measurement of the angiotensin-derived peptides as above) which are banked and are available for immediate analysis. With these, we aim to shed light on two questions that are plaguing the assessment and treatment of patients with COVID-19: 1) Does use of NSAIDs increase risk of severe complications from COVID-19? 2) Are patients with asthma and Type 2 respiratory inflammation at increased risk of severe complications from COVID-19? Completion of these aims would allow us to make recommendations regarding safety of NSAID use in COVID-19. Many patients are currently choosing to stop their regularly prescribed aspirin and NSAIDs out of fear, which we suspect is unfounded. We will also further understand whether patients with severe Type 2 respiratory inflammation have different nasal ACE2 expression and angiotensin peptide levels, compared to healthy controls, which would suggest a differing risk of severe COVID-19 in those patients.
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Control of Pulmonary Inflammation by Leukotriene E4
  • 批准号:
    10296403
  • 项目类别:
  • 资助金额:
    $70.07万
  • 财政年份:
    2021
  • 负责人:
    Joshua A Boyce
  • 依托单位:
Control of Pulmonary Inflammation by Leukotriene E4
  • 批准号:
    10468771
  • 项目类别:
  • 资助金额:
    $70.07万
  • 财政年份:
    2021
  • 负责人:
    Joshua A Boyce
  • 依托单位:
Control of Pulmonary Inflammation by Leukotriene E4
  • 批准号:
    10666460
  • 项目类别:
  • 资助金额:
    $70.07万
  • 财政年份:
    2021
  • 负责人:
    Joshua A Boyce
  • 依托单位:
CysLT and P2Y Receptors in Lung Inflammation
  • 批准号:
    10321255
  • 项目类别:
  • 资助金额:
    $53.55万
  • 财政年份:
    2018
  • 负责人:
    Joshua A Boyce
  • 依托单位:
海外基金