Experimental and natural SARS-CoV-2 infection of the human pancreas

人类胰腺的实验性和自然 SARS-CoV-2 感染

基本信息

  • 批准号:
    10319841
  • 负责人:
  • 金额:
    $ 45.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-17 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT The possibility that infection with SARS-CoV-2 may trigger diabetes emerged as a concern in mid 2020. We have addressed this issue by developing a research roadmap that identified complementary areas of investigation according to several broad topics in the realm of relevant basic biomedical research. Based on our recent publication about the expression of SARS-CoV-2 entry factors in the non-diabetic human pancreas, we have now developed a Research Strategy that will assess the principal capacity of pancreatic SARS-CoV-2 infection and its primary consequences in a series of in vitro, in vivo and ex vivo studies distributed across three Specific Aims: In Aim 1 we will define expression patterns of ACE2 and other viral entry factors in dispersed human pancreatic cell populations; will subject islets to in vitro SARS-CoV-2 infection and quantify infection patterns as well as alterations of single-cell proteomes and transcriptomes by flow cytometry, high-dimensional mass cytometry, and scRNAseq; will determine functional islet responses under conditions of viral infection by dynamic glucose-stimulated insulin secretion; will conduct mechanistic studies with targeted ACE2 blockade and by generation of ACE2-deficient beta-like cells; and will explore SARS-CoV-2 infection in the context of living pancreas slices that provide a more “physiological” experimental platform for in vitro studies. In Aim 2, we will use the robust “minimal mass” model of human islet transplantation into immunodeficient mice to delineate metabolic perturbations (blood glucose values, plasma insulin, intraperitoneal glucose tolerance test) accrued in the wake of an in vivo SARS-CoV-2 challenge. To address the considerable experimental and logistical challenges in these studies, we have developed a tiered approach that progressively refines experimental designs (including use of a recently generated, sequenced and characterized mouse-adapted [ma] SARS-CoV-2 strain) with the goal to imbue our models with escalating biological relevance. In Aim 3, we will draw on our access to COVID-19 and control autopsy cases to reveal the ex vivo viral burden of natural SARS-CoV-2 infection in the pancreas. These studies, which build on recently published pilot data as well as extensive preparatory studies to adjust our staining protocols to the demands of at times suboptimal tissue quality, will define SARS-CoV-2 protein and mRNA abundance, cellular association and distribution patterns across the COVID-19 pancreas. We will further leverage an established immunohistochemical multiplexing strategy to define the identity, quantity and distribution of major immune cell subsets throughout COVID-19 and control pancreata. Thus, the proposed work will generate an inclusive perspective on the cardinal viral and immunological components of the potentially altered pancreatic histology in COVID-19. Collectively, the proposed work addresses, and is expected to resolve at least in part, key aspects of the hypothesis that SARS-CoV-2 infection may precipitate diabetes onset. Together with emerging epidemiological data, it may therefore provide an important foundation for future risk assessment and the prioritization of prophylactic and/or therapeutic intervention strategies.
摘要

项目成果

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DIRK HOMANN其他文献

DIRK HOMANN的其他文献

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{{ truncateString('DIRK HOMANN', 18)}}的其他基金

Experimental and natural SARS-CoV-2 infection of the human pancreas
人类胰腺的实验性和自然 SARS-CoV-2 感染
  • 批准号:
    10490319
  • 财政年份:
    2021
  • 资助金额:
    $ 45.33万
  • 项目类别:
Experimental and natural SARS-CoV-2 infection of the human pancreas
人类胰腺的实验性和自然 SARS-CoV-2 感染
  • 批准号:
    10681444
  • 财政年份:
    2021
  • 资助金额:
    $ 45.33万
  • 项目类别:
Integrated Functional Histopathology of the Diabetic Human Pancreas
糖尿病人胰腺的综合功能组织病理学
  • 批准号:
    10306379
  • 财政年份:
    2017
  • 资助金额:
    $ 45.33万
  • 项目类别:
Integrated Functional Histopathology of the Diabetic Human Pancreas
糖尿病人胰腺的综合功能组织病理学
  • 批准号:
    9426105
  • 财政年份:
    2017
  • 资助金额:
    $ 45.33万
  • 项目类别:
Integrated Functional Histopathology of the Diabetic Human Pancreas
糖尿病人胰腺的综合功能组织病理学
  • 批准号:
    10058240
  • 财政年份:
    2017
  • 资助金额:
    $ 45.33万
  • 项目类别:
Decay accelerating factor dependent inhibition of T cell immunity
T 细胞免疫的衰变加速因子依赖性抑制
  • 批准号:
    9165635
  • 财政年份:
    2016
  • 资助金额:
    $ 45.33万
  • 项目类别:
Decay accelerating factor dependent inhibition of T cell immunity
T 细胞免疫的衰变加速因子依赖性抑制
  • 批准号:
    9282415
  • 财政年份:
    2016
  • 资助金额:
    $ 45.33万
  • 项目类别:
Regulation of Pathogen-specific T Cell Immunity by Adenosine Generation
通过腺苷生成调节病原体特异性 T 细胞免疫
  • 批准号:
    9001889
  • 财政年份:
    2014
  • 资助金额:
    $ 45.33万
  • 项目类别:
Regulation of Pathogen-specific T Cell Immunity by Adenosine Generation
通过腺苷生成调节病原体特异性 T 细胞免疫
  • 批准号:
    8848512
  • 财政年份:
    2014
  • 资助金额:
    $ 45.33万
  • 项目类别:
Regulation of pathogen-specific T cell immunity by adenosine generation
通过腺苷生成调节病原体特异性 T 细胞免疫
  • 批准号:
    8418688
  • 财政年份:
    2012
  • 资助金额:
    $ 45.33万
  • 项目类别:

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