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
- 来源:
- 关键词:2019-nCoVAdultAnimalsAutoimmune ProcessAutopsyBeta CellCOVID-19COVID-19 pandemicCell SurvivalCell physiologyCellsCessation of lifeChemicalsClinicalClinical ResearchColonCoronavirusCoxsackie B VirusesCytomegalovirusDefectDevelopmentDiabetes MellitusDiseaseEndocrineEnterovirusEventFDA approvedFamilyFunctional disorderHumanImatinibImpairmentIn VitroIndividualInfectionInstitutional Review BoardsInsulinInsulin ResistanceInsulin-Dependent Diabetes MellitusIslet CellIslets of LangerhansLungMedicineMetabolicMetallothioneinMicroscopyMumps virusMycophenolic AcidNewly DiagnosedNon-Insulin-Dependent Diabetes MellitusOrganoidsOutcomePancreasPathogenesisPathogenicityPatientsPharmaceutical PreparationsPhenotypePlayProtocols documentationQuantitative Reverse Transcriptase PCRResearch PersonnelRisk FactorsRoleRotavirusSamplingStructure of beta Cell of isletTestingTherapeuticTissue SampleTissuesTranscriptUp-RegulationVirusVirus DiseasesWorld Health Organizationchemokinedrug candidatehuman pluripotent stem cellhumanized mouseisletmouse modelmultidisciplinarynovel strategiesnovel therapeuticspandemic diseasephysiologic modelstem cellstranscriptome sequencing
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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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