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: 10319780
• 负责人: Shuibing Chen
• 金额: $ 44.01万
• 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/10319780
• 关键词: 2019-nCoV; ACE2; Acinar Cell; Alpha Cell; Autopsy; Beta Cell; Blood Vessels; COVID-19; COVID-19 detection; COVID-19 mortality; COVID-19 pandemic; COVID-19 patient; COVID-19 susceptibility; Cell physiology; Cells; Cellular Stress Response; Cessation of life; Clinical; Clinical Data; Clinical Research; 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; 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; Tumor-infiltrating immune cells; Virus; autoimmune pathogenesis; base; chemokine; coronavirus disease; high risk; imaging system; islet; macrophage; 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.

抽象的。 最近的临床数据表明，冠状病毒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，Covid-19 死亡率 有症状 。相反，新的糖尿病和严重 ，面临更高的风险 在Covid-19患者中已经观察到已经存在的糖尿病的代谢并发症。因此，有一个 强烈需要了解Covid-19患者胰腺功能障碍的病理和机制。这里， 我们证明了来自Covid-19 患者。单细胞RNA-seq和免疫染色证实了多种类型的胰岛细胞是 易受SARS-COV-2的影响，引起细胞应激反应和趋化因子的诱导。在sars上 - COV-2感染，β细胞显示胰岛素表达降低，并且α和 腺泡细胞标记，包括胰高血糖素和PRSS1/胰蛋白酶1，表明细胞 转变。 Hyperion技术检查尸检样品的发病机理 Covid-19患者。此外，我们将使用人类胰岛和血管化的人类胰腺器官 系统地评估直接感染和旁分泌炎症信号对人的作用的模型 内分泌细胞的细胞身份，功能和存活。 在提案中，我们将应用最新 通过这项研究，我们希望提供 系统概述Covid-19患者胰腺的病理变化，以及详细的 了解内分泌细胞功能障碍的机制，这将为新颖的发展铺平道路 治疗可保护COVID-19患者的内分泌细胞功能。