Administrative Core

项目总结 由于新冠肺炎，SARS-CoV-2大流行已导致全球范围内的大规模发病率和死亡率， 美国受到的影响尤为严重。新冠肺炎的危险因素包括男性、高龄和肥胖。 在其他因素中，这也是巴雷特食道(BE)和食管腺癌的关键危险因素 (东区议会)。因此，BE患者感染SARS-CoV-2的比率可能会明显高于 普通民众。因此，BE患者感染SARS-CoV-2的几率可能会明显更高。 与普通人群相比。SARS-CoV-2通过结合血管紧张素转换途径感染细胞 酶2受体与跨膜型丝氨酸蛋白酶2对病毒刺突蛋白的裂解 (TMPRSS2)。感染诱导关键途径和下游效应器，导致明显的炎症。 血管紧张素转换酶2在食道组织中高表达，血管紧张素转换酶抑制剂降低BE中NF-κB蛋白的表达，以及 血管紧张素转换酶抑制剂的使用与降低EAC的风险有关。因此，有可能SARS-CoV-2在中国的感染 BE患者可对BE组织产生直接影响，从而加速肿瘤的形成。我们发表了一篇回顾展 对1,600名住院新冠肺炎患者进行的队列研究发现，组胺-2受体的使用 拮抗剂法莫替丁与死亡风险降低2倍相关。虽然潜在的机制 基于这一观察结果仍然知之甚少，法莫替丁不仅可能改善短期临床 这些患者的预后，但也改善了BE中SARS-CoV-2的促肿瘤作用。质子泵 在队列研究中，抑制剂(PPI)与较差的结果相关，我们之前曾表明PPI 给药会导致肠道微生物体内肾素-血管紧张素途径的增加。因此，我们 假设如下：1)有新冠肺炎病史的患者进展为 对于有记录的COVID病史的BE患者，可以用法莫替丁代替PPI。 19.在这项提案中，我们将解决以下具体目标：目标1)界定ACE2的职能作用 和TMPRSS2在BE和EAC细胞中的表达；目的2)确定法莫替丁是否影响SARS-CoV-2 BE和EAC细胞的感染；目的3)评估TMPRSS2和ACE2表达的关系 和BE中的免疫细胞群。新冠肺炎的病史可能代表着一种新的风险标志 在BE患者中进展为EAC，这可能需要纳入旨在 确定适当的高危患者进行筛查和监测。此外，用法莫替丁治疗 而非PPI可能更适合于有轻度反流症状和有病史的BE患者 新冠肺炎。

PROJECT SUMMARY The SARS-CoV-2 pandemic has led to massive morbidity and mortality worldwide due to COVID-19, with the United States particularly affected. Risk factors for COVID-19 include male sex, older age, and obesity, amongst others, which are also key risk factors for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). Thus, patients with BE will likely be infected with SARS-CoV-2 at markedly higher rates compared to the general population. Thus, patients with BE will likely be infected with SARS-CoV-2 at markedly higher rates compared to the general population. SARS-CoV-2 infects cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor and subsequent viral spike protein cleaving by transmembrane serine protease 2 (TMPRSS2). Infection induces key pathways and downstream effectors, resulting in pronounced inflammation. ACE2 is highly expressed in esophageal tissue, ACE inhibitors reduce NF-κB protein expression in BE, and ACE inhibitor use is associated with reduced risk of EAC. It is therefore plausible that SARS-CoV-2 infection in BE patients can result in direct effects on BE tissues that accelerate neoplasia. We published a retrospective cohort study of >1,600 hospitalized COVID-19 patients and found that use of the histamine-2 receptor antagonist famotidine was associated with a >2-fold reduction in the risk of death. While potential mechanisms underlying this observation remain poorly understood, famotidine may not only improve short-term clinical outcomes in these patients but also ameliorate the pro-neoplastic effects of SARS-CoV-2 in BE. Proton pump inhibitors (PPIs) were associated with worse outcomes in the cohort study, and we previously showed that PPI administration leads to increases in the renin-angiotensin pathway in the gut microbiome. Thus, we hypothesize the following: 1) BE patients with a history of COVID-19 are at increased risk for progression to EAC; and 2) famotidine may be indicated instead of PPIs for BE patients with a documented history of COVID- 19. In this proposal we will address the following specific aims: Aim 1) To define the functional role of ACE2 and TMPRSS2 in BE and EAC cells; Aim 2) To determine whether famotidine influences SARS-CoV-2 infection in BE and EAC cells; Aim 3) To assess the relationship between TMPRSS2 and ACE2 expression and immune cell populations in BE. A history of COVID-19 may represent a novel marker for risk for progression to EAC among BE patients, and this may need to be incorporated into clinical profiles aimed at identifying appropriate high-risk patients for screening and surveillance. Furthermore, treatment with famotidine and not PPIs may be more appropriate for BE patients with mild reflux symptoms and a history of documented COVID-19.