Mechanistic characterization of SARS-CoV2 associated kidney injury
Mechanistic characterization of SARS-CoV2 associated kidney injury
批准号:
10427448
负责人:
Deborah J Lenschow
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
项目状态:
已结题
起止时间:
2021-06-11 至 2024-04-30
关键词:
2019-nCoVAcuteAcute Renal Failure with Renal Papillary NecrosisAcute Respiratory Distress SyndromeAgeApoptosisCOVID-19COVID-19 complicationsCOVID-19 patientCRISPR screenCaspaseCell DeathCellsCessation of lifeClinical ResearchClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesCohort AnalysisComplexCoronavirusDataDiseaseEtiologyFunctional disorderGenesGoalsHMGB1 geneHistopathologyHumanISG15 geneIn VitroIndividualInfectionInflammationInflammatoryInflammatory ResponseInjuryInjury to KidneyIntegration Host FactorsInterferonsK-18 conjugateKidneyKnockout MiceLungMapsMediatingModelingMolecularMusOrganOrganoidsPathogenesisPathway interactionsPatientsPatternPersonsPlayPredispositionProductionProtein KinaseProteinsPulmonary InflammationRIPK1 geneRegulationReperfusion InjuryReportingRisk FactorsRoleSARS coronavirusSARS-CoV-2 infectionSARS-CoV-2 pathogenesisSerumSeverity of illnessSourceSystemTestingTherapeuticTracheal EpitheliumTransgenic MiceTropismTubular formationUbiquitin Like ProteinsUnited StatesViralViral Load resultViral ProteinsVirusVirus DiseasesWorkbasecell injurychemokinecytokinecytokine release syndromeeffective interventiongenome-widehuman coronavirusin vivoinduced pluripotent stem cellinsightkidney cellkidney epithelial cellmortality riskmouse modelnovelrenal damageresponsesevere COVID-19systemic inflammatory responsetherapeutic development
中文摘要
SARS-CoV 2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)。
19)。目前,美国有超过1650万人确认感染了SARS-CoV 2,
都死了重症COVID-19的特征是肺部和全身炎症以及多器官
严重的COVID患者中有很大一部分发生急性肾损伤。机制
SARS-CoV 2是如何引发这种严重的发病机制尚不清楚。最近的临床研究
表明细胞死亡,特别是诱导坏死性凋亡,可能是严重COVID-19的预测因子
疾病宿主限制坏死性凋亡的机制尚不清楚。初步数据显示,
干扰素诱导蛋白ISG 15作为坏死性凋亡的负调节因子,
病毒感染时的炎症反应。我们还表明,ISG 15缺陷小鼠迅速死亡,
以大量释放促炎细胞因子为特征的肾缺血-再灌注损伤。
在本提案中,我们将检验ISG 15作为调节细胞凋亡的关键宿主限制因子的假设。
肾脏内程序性坏死性凋亡和下游炎症反应,以限制急性肾损伤
在SARS-CoV 2感染期间。我们将利用来源于诱导多能干细胞的肾类器官,
ISG 15已被CRISPR删除,CRISPR是一种与肾类器官和原代气管上皮共培养系统
培养物(hTECs)和SARS-CoV-2的体内小鼠模型,以提出几个问题,包括:1)SARS-
CoV 2通过直接病毒转导或响应系统性免疫应答诱导肾上皮细胞损伤。
炎症?2)ISG 15是否调节坏死性细胞死亡以及促炎细胞因子/趋化因子
SARS-CoV 2感染过程中肾脏上皮细胞的产生?3)坏死性凋亡及其调节是否
ISG 15与SARS-CoV 2感染时急性肾损伤有关?总的来说,我们的研究将提供重要的
深入了解限制坏死性凋亡的宿主因素,可能是严重COVID-19的重要因素
导致肾损伤。
英文摘要
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.
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会议论文
Mechanistic characterization of SARS-CoV2 associated kidney injury
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批准号:10319713
-
项目类别:
-
资助金额:$39.38万
-
财政年份:2021
-
负责人:Deborah J Lenschow
-
依托单位:
Mechanistic characterization of SARS-CoV2 associated kidney injury
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批准号:10619568
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项目类别:
-
资助金额:$39.38万
-
财政年份:2021
-
负责人:Deborah J Lenschow
-
依托单位:
Regulation of Cell Death and Inflammation by ISG15 during SARS-CoV2 Infection
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批准号:10287787
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项目类别:
-
资助金额:$19.69万
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财政年份:2021
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负责人:Deborah J Lenschow
-
依托单位:
Regulation of Cell Death and Inflammation by ISG15 during SARS-CoV2 Infection
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批准号:10424558
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项目类别:
-
资助金额:$23.63万
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财政年份:2021
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负责人:Deborah J Lenschow
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依托单位:
Washington University Rheumatic DiseasesResearch Resource-based Center
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批准号:10472003
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项目类别:
-
资助金额:$74.49万
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财政年份:2018
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负责人:Deborah J Lenschow
-
依托单位:
Washington University Rheumatic DiseasesResearch Resource-based Center
-
批准号:9764270
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项目类别:
-
资助金额:$77.29万
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财政年份:2018
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负责人:Deborah J Lenschow
-
依托单位:
Washington University Rheumatic DiseasesResearch Resource-based Center
-
批准号:10019327
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项目类别:
-
资助金额:$76.5万
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财政年份:2018
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负责人:Deborah J Lenschow
-
依托单位:
Washington University Rheumatic DiseasesResearch Resource-based Center
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批准号:10251236
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项目类别:
-
资助金额:$75.43万
-
财政年份:2018
-
负责人:Deborah J Lenschow
-
依托单位:
Washington University Rheumatic Diseases Research Resource-based Center
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批准号:10704273
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项目类别:
-
资助金额:$77.75万
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财政年份:2018
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负责人:Deborah J Lenschow
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依托单位:
REGULATION OF INFLUENZA VIRUS INFECTION BY ISG15
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批准号:8109260
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项目类别:
-
资助金额:$33.52万
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财政年份:2009
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负责人:Deborah J Lenschow
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依托单位:
REGULATION OF HOST RESPONSES TO RESPIRATORY VIRAL INFECTION BY ISG15
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批准号:9926208
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项目类别:
-
资助金额:$39.36万
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财政年份:2009
-
负责人:Deborah J Lenschow
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依托单位:
REGULATION OF INFLUENZA VIRUS INFECTION BY ISG15
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批准号:7564541
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项目类别:
-
资助金额:$34.2万
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财政年份:2009
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负责人:Deborah J Lenschow
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依托单位:
REGULATION OF INFLUENZA VIRUS INFECTION BY ISG15
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批准号:8305774
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项目类别:
-
资助金额:$33.52万
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财政年份:2009
-
负责人:Deborah J Lenschow
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依托单位:
REGULATION OF INFLUENZA VIRUS INFECTION BY ISG15
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批准号:7904131
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项目类别:
-
资助金额:$33.86万
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财政年份:2009
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负责人:Deborah J Lenschow
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依托单位:
Role of ISG15 in the Pathogenesis of SLE
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批准号:7680339
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项目类别:
-
资助金额:$9.18万
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财政年份:2008
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负责人:Deborah J Lenschow
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依托单位:
ISG15 REGULATION OF ANTIVIRAL IMMUNE RESPONSES
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批准号:7487917
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项目类别:
-
资助金额:$22.37万
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财政年份:2007
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负责人:Deborah J Lenschow
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依托单位:
Role of 1SG15 in the Pathogenesis of SLE
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批准号:7508978
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项目类别:
-
资助金额:$7.38万
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财政年份:2007
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负责人:Deborah J Lenschow
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依托单位:
ISG15 REGULATION OF ANTIVIRAL IMMUNE RESPONSES
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批准号:7391498
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项目类别:
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资助金额:$19.0万
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财政年份:2007
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负责人:Deborah J Lenschow
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依托单位:
Function of ISG15 during Viral Infection
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批准号:7013109
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项目类别:
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资助金额:$8.88万
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财政年份:2004
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负责人:Deborah J Lenschow
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依托单位:
Function of ISG15 during Viral Infection
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批准号:6879241
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项目类别:
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资助金额:$8.67万
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财政年份:2004
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负责人:Deborah J Lenschow
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依托单位:
海外基金