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

金属硫蛋白 1E 作为人胰腺 β 细胞功能和存活的中央调节剂

• 批准号: 10190924
• 负责人: Shuibing Chen
• 金额: $ 80.99万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190924
• 关键词: Beta Cell; Biological Process; Cell Death; Cell Survival; Cell physiology; Cells; Cellular Stress; Cessation of life; Complications of Diabetes Mellitus; Cues; Defect; Development; Diabetes Mellitus; Disease; Dose; FOXO1A gene; Family; Family member; Fatty Acids; Flow Cytometry; Functional disorder; Genes; Genetic Polymorphism; Glucose; Heterogeneity; Human; Image; Impairment; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Knowledge; Lead; Metabolic; Metallothionein; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathway interactions; Play; Protein Isoforms; Reporting; Role; Scheme; Signal Transduction; Stress; Structure of beta Cell of islet; System; Testing; Variant; diabetes mellitus therapy; drug development; endoplasmic reticulum stress; genetic variant; genome wide association study; high risk; human embryonic stem cell; human pluripotent stem cell; humanized mouse; immunocytochemistry; in vivo; insight; islet; member; mouse model; novel; novel marker; novel therapeutics; real time monitoring; single-cell RNA sequencing

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.

抽象。 COVID-19被世界卫生组织宣布为大流行病。COVID 19是由严重急性 呼吸道综合征冠状病毒2型（SARS-CoV-2），属于冠状病毒科，是一个多样化的家族， 导致人类和动物一系列疾病的病毒。最近的临床研究表明， 患有新冠肺炎和糖尿病其他研究表明，糖尿病不仅是严重COVID的风险因素， 19疾病，而且SARS-CoV-2感染可诱发新发糖尿病。然而，目前尚不清楚 糖尿病相关细胞被病毒感染，以及这些细胞如何对SARS-CoV-2感染作出反应。 许多研究支持病毒感染在1型糖尿病（T1 D）中起致病作用的假设。 从新诊断的T1 D患者中获得的肠道病毒分离株可在体外感染并破坏人胰岛细胞。 在T1 D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- 学科研究团队，包括专家β细胞生物学家（陈博士），干细胞生物学家（埃文斯博士和 Schwartz）和病毒学家（tenOever博士）系统地研究SARS-CoV-2对胰腺癌的影响。 内分泌细胞，并验证SARS-CoV-2感染导致人胰腺内分泌细胞 杀伤性在初步研究中，我们发现人多能干细胞（hPSC）来源的胰腺癌细胞在体外表达， 内分泌细胞允许SARS-CoV-2感染，这一点在成人原代人中得到了进一步验证。 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 趋化因子的显著上调，与COVID-19患者尸检后获得的组织概况相似。 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， 对hPSC衍生结肠和肺类器官均显示抗SARS-CoV-2活性。在此，我们建议 使用COVID-19患者的胰腺样本验证SARS-CoV-2感染，检查 SARS-CoV-2感染人类内分泌细胞，并重新使用FDA批准的药物来保护人类 SRAS-CoV-2感染的胰腺内分泌细胞。提出了三个目标： 目标1. COVID-19患者尸检胰腺样本中的SARS-CoV-2感染。 目标2.研究SARS-CoV-2感染对人类胰腺内分泌细胞功能和存活的影响。 目标3。重新利用FDA批准的药物来保护人类胰腺内分泌细胞免受SARS-CoV-2感染。 通过本研究，我们期望为SARS冠状病毒2型感染人类提供直接的致病性证据 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。