Mechanistic characterization of SARS-CoV2 associated kidney injury

SARS-CoV2相关肾损伤的机制特征

基本信息

  • 批准号:
    10427448
  • 负责人:
  • 金额:
    $ 39.38万
  • 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:
    2021-06-11 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

SARS-CoV2 is a highly contagious, novel human coronavirus that causes coronavirus disease 2019 (COVID- 19). Currently over 16.5 million people in the US have confirmed infection with SARS-CoV2 and over 300,000 have died. Severe COVID-19 is characterized by pulmonary and systemic inflammation and multi-organ dysfunction, with a significant portion of severe COVID patients developing acute kidney injury. The mechanism by which SARS-CoV2 triggers such severe pathogenesis is poorly understood. Recent clinical studies have suggested that cell death, especially the induction of necroptosis, may be a predictor of severe COVID-19 disease. The mechanism by which the host restricts necroptosis is unclear. In preliminary data we have shown that the interferon induced protein, ISG15, acts as a negative regulator of necroptosis and its downstream inflammatory responses during viral infection. We have also shown that ISG15 deficient mice rapidly succumb to ischemia-reperfusion injury of the kidney characterized by a massive release of proinflammatory cytokines. In this proposal we will test the hypothesis that ISG15 serves as a critical host restriction factor in regulating programmed necroptosis and downstream inflammatory responses within the kidney to limit acute kidney injury during SARS-CoV2 infection. We will utilize kidney organoids derived from induce pluripotent stem cells in which ISG15 has been deleted by CRISPR, a co-culture system with kidney organoids and primary tracheal epithelial cultures (hTECs), and in vivo mouse model of SARS-CoV-2 to ask several questions including: 1) Does SARS- CoV2 induce damage to kidney epithelial cells via direct viral transduction or in response to systemic inflammation?; 2) Does ISG15 modulate necroptotic cell death as well as proinflammatory cytokine/chemokine production in kidney epithelial cells during SARS-CoV2 infection?; 3) Does necroptosis and its regulation by ISG15 contribute to acute kidney injury during SARS-CoV2 infection? Overall, our studies will provide important insight into host factors that restrict necroptosis and could be an important contributor to severe COVID-19 induced kidney injury.
SARS-CoV2是一种高度传染性的新型人类冠状病毒,可导致2019年冠状病毒病(COVID- 19)。目前,美国已有超过1650万人确认感染了SARS-CoV2病毒,其中超过30万人感染了SARS-CoV2 都死了。重症新冠肺炎以肺部和全身炎症、多器官损害为特征 严重的COVID患者中有很大一部分会出现急性肾损伤。这一机制 SARS-CoV2通过什么机制触发如此严重的发病机制尚不清楚。最近的临床研究表明 提示细胞死亡,尤其是坏死性下垂的诱导,可能是严重新冠肺炎的一个预测因子 疾病。宿主限制坏死性下垂的机制尚不清楚。在初步数据中,我们已经显示 干扰素诱导蛋白ISG15对坏死性下垂及其下游起负调节作用 病毒感染时的炎症反应。我们还发现ISG15基因缺陷的小鼠会迅速死亡 以促炎症细胞因子大量释放为特征的肾脏缺血再灌注损伤。 在这项建议中,我们将检验ISG15作为关键的宿主限制因子在调节 程序性坏死性下垂和肾脏下游炎症反应限制急性肾损伤 在SARS-CoV2感染期间。我们将利用从诱导多能干细胞中提取的肾脏器官类物质 ISG15已被CRISPR删除,CRISPR是一种与肾脏器官和原代气管上皮共同培养的系统 培养(HTECs),并在体内建立SARS-CoV-2小鼠模型,提出几个问题,包括:1)SARS- CoV2通过直接病毒转导或全身性免疫应答诱导肾上皮细胞损伤 炎症?;2)ISG15是否与促炎细胞因子/趋化因子一样调节坏死性细胞死亡 SARS-CoV2感染过程中肾上皮细胞产生?;3)坏死性下垂及其调节 ISG15在SARS-CoV2感染中导致急性肾损伤吗?总体而言,我们的研究将提供重要的 洞察限制坏死性下垂的宿主因素可能是严重新冠肺炎的重要因素 致肾损伤。

项目成果

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Deborah J Lenschow其他文献

Deborah J Lenschow的其他文献

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{{ truncateString('Deborah J Lenschow', 18)}}的其他基金

Mechanistic characterization of SARS-CoV2 associated kidney injury
SARS-CoV2相关肾损伤的机制特征
  • 批准号:
    10319713
  • 财政年份:
    2021
  • 资助金额:
    $ 39.38万
  • 项目类别:
Mechanistic characterization of SARS-CoV2 associated kidney injury
SARS-CoV2相关肾损伤的机制特征
  • 批准号:
    10619568
  • 财政年份:
    2021
  • 资助金额:
    $ 39.38万
  • 项目类别:
Regulation of Cell Death and Inflammation by ISG15 during SARS-CoV2 Infection
SARS-CoV2 感染期间 ISG15 对细胞死亡和炎症的调节
  • 批准号:
    10287787
  • 财政年份:
    2021
  • 资助金额:
    $ 39.38万
  • 项目类别:
Regulation of Cell Death and Inflammation by ISG15 during SARS-CoV2 Infection
SARS-CoV2 感染期间 ISG15 对细胞死亡和炎症的调节
  • 批准号:
    10424558
  • 财政年份:
    2021
  • 资助金额:
    $ 39.38万
  • 项目类别:
Washington University Rheumatic DiseasesResearch Resource-based Center
华盛顿大学风湿病研究资源中心
  • 批准号:
    10472003
  • 财政年份:
    2018
  • 资助金额:
    $ 39.38万
  • 项目类别:
Washington University Rheumatic DiseasesResearch Resource-based Center
华盛顿大学风湿病研究资源中心
  • 批准号:
    9764270
  • 财政年份:
    2018
  • 资助金额:
    $ 39.38万
  • 项目类别:
Washington University Rheumatic DiseasesResearch Resource-based Center
华盛顿大学风湿病研究资源中心
  • 批准号:
    10019327
  • 财政年份:
    2018
  • 资助金额:
    $ 39.38万
  • 项目类别:
Washington University Rheumatic DiseasesResearch Resource-based Center
华盛顿大学风湿病研究资源中心
  • 批准号:
    10251236
  • 财政年份:
    2018
  • 资助金额:
    $ 39.38万
  • 项目类别:
Washington University Rheumatic Diseases Research Resource-based Center
华盛顿大学风湿病研究资源中心
  • 批准号:
    10704273
  • 财政年份:
    2018
  • 资助金额:
    $ 39.38万
  • 项目类别:
REGULATION OF INFLUENZA VIRUS INFECTION BY ISG15
ISG15 对流感病毒感染的监管
  • 批准号:
    8109260
  • 财政年份:
    2009
  • 资助金额:
    $ 39.38万
  • 项目类别:

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