Metallothionein 1E as a Central Regulator of Human Pancreatic Beta Cell Function and Survival

抽象的。 新冠肺炎被世界卫生组织宣布为大流行。COVID19是由严重急性呼吸综合征引起的 呼吸综合征冠状病毒2(SARS-CoV-2)，属于冠状病毒科，是一个多样性的家族。 在人类和动物中引起一系列疾病的病毒。最近的临床研究表明两者之间存在很强的联系 新冠肺炎和糖尿病。其他研究表明，糖尿病不仅是严重COVID的危险因素-- 19种疾病，也说明SARS-CoV-2感染可以诱发新的糖尿病发作。然而，目前还不清楚是什么 糖尿病相关细胞被病毒感染，以及这些细胞如何应对SARS-CoV-2感染。 许多研究支持病毒感染在1型糖尿病(T1D)中起致病作用的假设。 从新诊断的T1D患者中分离到的肠道病毒在体外可以感染和破坏人的胰岛细胞。 在T1D患者中，由于自身免疫破坏，β细胞质量减少。在这里，我们组装了一个多- 纪律调查组，包括专家贝塔细胞生物学家(陈博士)、干细胞生物学家(埃文斯博士和 Schwartz)和一位病毒学家(TenOever博士)系统地研究SARS-CoV-2对胰腺的影响 内分泌细胞，并验证SARS-CoV-2感染导致人胰腺内分泌细胞的假设 毁灭。在初步研究中，我们发现人多能干细胞(HPSC)来源的胰腺 内分泌细胞对SARS-CoV-2感染是允许的，这一点在成人原代人类身上得到了进一步的验证 小岛。SARS-CoV-2感染hPSC来源的胰腺内分泌细胞后的转录谱显示 趋化因子显著上调，类似于新冠肺炎患者尸检后获得的组织图谱。 此外，我们进行了两次高含量的化学筛选，并确定了几种FDA批准的药物 在hPSC来源的结肠和肺器官上显示抗SARS-CoV-2活性。在此，我们建议 用新冠肺炎患者的胰腺样本验证SARS-CoV-2感染，检查 SARS-CoV-2对人内分泌细胞的感染及FDA批准的药物再利用保护人类 SRAS-CoV-2感染的胰腺内分泌细胞提出了三个目标： 目的1.验证新冠肺炎患者死后胰腺标本中是否存在SARS-CoV-2感染。 目的2.检测SARS-CoV-2感染对人胰腺内分泌细胞功能和存活的影响。 目的3.将FDA批准的药物重新用于保护人胰腺内分泌细胞免受SARS-CoV-2感染。 通过这项研究，我们希望为人类感染SARS-CoV-2提供直接的病原学证据。 胰腺内分泌细胞，了解SARS-CoV-2感染胰腺内分泌细胞的发病机制， 并开发新的方法来保护人类内分泌细胞免受SARS-CoV-2感染。

Abstract. COVID-19 was declared a pandemic by the World Health Organization. COVID19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the coronaviridae, a diverse family of viruses that cause a range of diseases in humans and animals. Recent clinical studies show a strong association with COVID-19 and diabetes. Additional studies suggest that diabetes is not only a risk factor for severe COVID- 19 disease but also that SARS-CoV-2 infection can induce a new onset diabetes. However, it is not clear what diabetes-associated cells are infected by the virus and how these cells respond to SARS-CoV-2 infection. A number of studies support the hypothesis that viral infections play a causative role in Type 1 diabetes (T1D). Enterovirus isolates obtained from newly diagnosed T1D patients can infect and destroy human islet cells in vitro. In T1D patients, beta cell mass decreases due to auto-immune destruction. Here, we assemble a multi- disciplinary investigator team, including expert beta cell biologist (Dr. Chen), stem cell biologists (Drs. Evans and Schwartz), and a virologist (Dr. tenOever) to systematically study the impact of SARS-CoV-2 on pancreatic endocrine cells and test the hypothesis that SARS-CoV-2 infection causes human pancreatic endocrine cell destruction. In preliminary studies, we found that human pluripotent stem cell (hPSC)-derived pancreatic endocrine cells are permissive to SARS-CoV-2 infection, which was further validated using adult primary human islets. Transcript profiling following SARS-CoV-2 infection of hPSC-derived pancreatic endocrine cells revealed striking upregulation of chemokines, similar to profiles of tissues obtained after autopsy of COVID-19 patients. In addition, we performed two high content chemical screens and identified several FDA-approved drugs that show anti-SARS-CoV-2 activities on both hPSC-derived colonic and lung organoids. Here, we propose to validate the SARS-CoV-2 infection using pancreatic samples from COVID-19 patients, examine the impact of SARS-CoV-2 infection on human endocrine cells, and re-purpose FDA-approved drugs to protect human pancreatic endocrine cells from SRAS-CoV-2 infection. Three aims are proposed: Aim 1. Validate SARS-CoV-2 infection in pancreatic samples from post-mortem COVID-19 patients. Aim 2. Examine the impact of SARS-CoV-2 infection on human pancreatic endocrine cell function and survival. Aim 3. Repurpose FDA-approved drugs to protect human pancreatic endocrine cells from SARS-CoV-2 infection. Through this study, we expect to provide direct pathogenic evidence of SARS-CoV-2 infection of human pancreatic endocrine cells, understand the pathogenesis of SARS-CoV-2 infected pancreatic endocrine cells, and develop novel approaches to protect human endocrine cells from SARS-CoV-2 infection.