Decode the Impact of SARS-CoV-2 on Human Pancreas

解读 SARS-CoV-2 对人类胰腺的影响

• 批准号: 10646228
• 负责人: Shuibing Chen
• 金额: $ 42.26万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646228
• 关键词: 2019-nCoV; ACE2; Acinar Cell; Alpha Cell; Autopsy; Beta Cell; COVID-19; COVID-19 detection; COVID-19 impact; COVID-19 mortality; COVID-19 pandemic; COVID-19 patient; COVID-19 susceptibility; Cell physiology; Cells; Cellular Stress; Cessation of life; Clinical; Clinical Data; Clinical Research; Compensation; Cytokine Signaling; Cytometry; Data; Defect; Development; Diabetes Mellitus; Disease; Ductal Epithelial Cell; Endocrine; Endothelial Cells; Eukaryotic Initiation Factor-2; Event; Functional disorder; Glucagon; Human; Image; Impairment; Individual; Infection; Inflammation; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Laboratories; Macrophage; Metabolic; Modeling; Morbid Obesity; NRP1 gene; Non-Insulin-Dependent Diabetes Mellitus; Organoids; Outcome; Pancreas; Pancreatic duct; Paracrine Communication; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Publishing; Research Personnel; Risk Factors; Role; SARS-CoV-2 infection; Sampling; Signal Transduction; Specimen; Structure of beta Cell of islet; Technology; Testing; Therapeutic; Tissues; Trypsin; Vascularization; Virus; autoimmune pathogenesis; chemokine; high risk; imaging system; immune cell infiltrate; islet; multidisciplinary; novel therapeutics; pandemic disease; paracrine; physiologic model; severe COVID-19; single-cell RNA sequencing; stem cells; transdifferentiation

Abstract. Recent clinical data has suggested a bidirectional interaction between Coronavirus disease 19 (COVID-19) and diabetes. Individuals with diabetes and severe obesity are more likely to be complications, and have a higher COVID-19 mortality rate symptomatic . Conversely, new-onset diabetes and severe , are at a higher risk for metabolic complications of pre-existing diabetes have been observed in COVID-19 patients. Thus, there is a strong need to understand the pathology and mechanism of pancreatic dysfunction in COVID-19 patients. Here, we demonstrate the detection of SARS-CoV-2 in pancreatic endocrine cells in autopsy samples from COVID-19 patients. Single cell RNA-seq and immunostaining confirmed that multiple types of pancreatic islet cells are susceptible to SARS-CoV-2, eliciting a cellular stress response and the induction of chemokines. Upon SARS- CoV-2 infection, beta cells show a decreased expression of insulin and the increased expression of alpha and acinar cell markers, including glucagon and PRSS1/trypsin1, respectively, suggesting cellular transdifferentiation. Hyperion technology to examine the pathogenesis of autopsy samples of COVID-19 patients. In addition, we will use human islets and a vascularized human pancreatic organoid models to systematically evaluate the role of direct infection and paracrine inflammation signal on human endocrine cells cellular identities, function and survival. In the proposal, we will apply state-of-art Through this study, we would expect to provide a systematic overview of the pathological changes in the pancreas of COVID-19 patients, as well as a detailed mechanism to understand endocrine cell dysfunction, which will pave the road to the development of novel therapy to protect endocrine cell function in COVID-19 patients.

抽象。 最近的临床数据表明，冠状病毒疾病19（COVID-19）和 糖尿病 患有糖尿病和严重肥胖的人更有可能 并发症，并有较高的COVID-19 死亡率 症状性 .相反，新发糖尿病和严重 的风险更高， 已在COVID-19患者中观察到既存糖尿病的代谢并发症。由此可见，有一 强烈需要了解COVID-19患者胰腺功能障碍的病理和机制。在这里， 我们证明了在COVID-19尸检样本的胰腺内分泌细胞中检测到SARS-CoV-2 患者单细胞RNA-seq和免疫染色证实，多种类型的胰岛细胞是 对SARS-CoV-2易感，引发细胞应激反应和诱导趋化因子。在SARS期间- CoV-2感染后，β细胞显示胰岛素表达减少，α和β细胞表达增加。 腺泡细胞标志物，分别包括胰高血糖素和PRSS 1/胰蛋白酶1，提示细胞 转分化 尸检标本致病性检验的自动化技术 COVID-19患者。此外，我们将使用人类胰岛和血管化的人类胰腺类器官 系统评价直接感染和旁分泌炎症信号在人类 内分泌细胞的细胞特性、功能和存活。 在提案中，我们将采用最先进的 通过这项研究，我们希望提供一个 系统概述了COVID-19患者胰腺的病理变化，并详细介绍了 了解内分泌细胞功能障碍的机制，这将为开发新的 保护COVID-19患者内分泌细胞功能的治疗。

项目成果

A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants.

• DOI: 10.1016/j.stem.2022.09.008
• 发表时间: 2022-10-06
• 期刊: CELL STEM CELL
• 影响因子: 23.9
• 作者: Han, Yuling;Tan, Lei;Zhou, Ting;Yang, Liuliu;Carrau, Lucia;Lacko, Lauretta A.;Saeed, Mohsan;Zhu, Jiajun;Zhao, Zeping;Nilsson-Payant, Benjamin E.;Neto, Filipe Tenorio Lira;Cahir, Clare;Giani, Alice Maria;Chai, Jin Chou;Li, Yang;Dong, Xue;Moroziewicz, Dorota;Paull, Daniel;Zhang, Tuo;Koo, Soyeon;Tan, Christina;Danziger, Ron;Ba, Qian;Feng, Lingling;Chen, Zhengming;Zhong, Aaron;Wise, Gilbert J.;Xiang, Jenny Z.;Wang, Hui;Schwartz, Robert E.;tenOever, Benjamin R.;Noggle, Scott A.;Rice, Charles M.;Qi, Qibin;Evans, Todd;Chen, Shuibing
• 通讯作者: Chen, Shuibing

Human pluripotent-stem-cell-derived organoids for drug discovery and evaluation.

• DOI: 10.1016/j.stem.2023.04.011
• 发表时间: 2023-05-04
• 期刊: CELL STEM CELL
• 影响因子: 23.9
• 作者: Vandana, J. Jeya;Manrique, Cassandra;Lacko, Lauretta A.;Chen, Shuibing
• 通讯作者: Chen, Shuibing