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

基本信息

  • 批准号:
    10220173
  • 负责人:
  • 金额:
    $ 39.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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以在体外感染并破坏人类胰岛细胞。 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。

项目成果

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Shuibing Chen其他文献

Shuibing Chen的其他文献

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{{ truncateString('Shuibing Chen', 18)}}的其他基金

Abnormal Extracellular Vesicles and Particles from Human Islets Impact T1D progression
来自人类胰岛的异常细胞外囊泡和颗粒影响 T1D 进展
  • 批准号:
    10754074
  • 财政年份:
    2023
  • 资助金额:
    $ 39.77万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 39.77万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 39.77万
  • 项目类别:
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:
    10443871
  • 财政年份:
    2021
  • 资助金额:
    $ 39.77万
  • 项目类别:
A High Content Chemical Screen to Identify the Drug Candidates Promoting Human Beta Cell Proliferation
用于鉴定促进人类β细胞增殖的候选药物的高内涵化学筛选
  • 批准号:
    10343755
  • 财政年份:
    2020
  • 资助金额:
    $ 39.77万
  • 项目类别:
A High Content Chemical Screen to Identify the Drug Candidates Promoting Human Beta Cell Proliferation
用于鉴定促进人类β细胞增殖的候选药物的高内涵化学筛选
  • 批准号:
    10571823
  • 财政年份:
    2020
  • 资助金额:
    $ 39.77万
  • 项目类别:
A High Content Chemical Screen to Identify the Drug Candidates Promoting Human Beta Cell Proliferation
用于鉴定促进人类β细胞增殖的候选药物的高内涵化学筛选
  • 批准号:
    10117247
  • 财政年份:
    2020
  • 资助金额:
    $ 39.77万
  • 项目类别:
Determining the Intrinsic and Environmental Signal Contributing to Early T1D Progression
确定导致早期 T1D 进展的内在信号和环境信号
  • 批准号:
    10262967
  • 财政年份:
    2020
  • 资助金额:
    $ 39.77万
  • 项目类别:
Determining the Intrinsic and Environmental Signal Contributing to Early T1D Progression
确定导致早期 T1D 进展的内在信号和环境信号
  • 批准号:
    10440517
  • 财政年份:
    2020
  • 资助金额:
    $ 39.77万
  • 项目类别:
Determining the Intrinsic and Environmental Signal Contributing to Early T1D Progression
确定导致早期 T1D 进展的内在信号和环境信号
  • 批准号:
    10157473
  • 财政年份:
    2020
  • 资助金额:
    $ 39.77万
  • 项目类别:

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