课题基金 / 基金详情

Mechanisms of atherosclerotic cardiovascular complications in COVID19

Mechanisms of atherosclerotic cardiovascular complications in COVID19
新冠肺炎动脉粥样硬化性心血管并发症的机制
批准号:
10512449
负责人:
Chiara Giannarelli
金额:
$80.37万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-01 至 2026-08-31
关键词:
2019-nCoVACE2AcuteAddressAdverse effectsAffectAntiviral AgentsArterial Fatty StreakAtherosclerosisAutopsyBiological AssayBloodBlood CirculationBlood VesselsBone MarrowCOVID-19COVID-19 impactCOVID-19 pandemicCOVID-19 patientCOVID-19 treatmentCardiovascular systemCellsClinical SciencesDataDetectionDisease ProgressionEventExposure toFoam CellsFutureGenesGoalsHamstersHeartHematopoieticHistologicHumanImmuneImmune responseImmunofluorescence ImmunologicInfectionInflammationInflammatoryInflammatory ResponseInterleukin-1 betaInterleukin-6KnowledgeLungMeasuresMediatingMedical centerMesocricetus auratusModelingMolecularMonitorMyocardial InfarctionNRP1 geneNeuropilin-1New York CityNucleocapsid ProteinsOrganOutcomePTPRC genePatientsPost-Acute Sequelae of SARS-CoV-2 InfectionPublic HealthRecoveryResolutionRiskRoleSARS-CoV-2 infectionSpleenStrokeTestingTissuesUnited States National Institutes of HealthViralVirusVirus ReplicationWorkX-Ray Computed Tomographyacute coronary syndromeacute infectionatherogenesisbasebiobankcardiovascular risk factorclinically relevantcoronavirus diseasecytokinedesignfluorodeoxyglucosefluorodeoxyglucose positron emission tomographyglobal healthhuman RNA sequencinghuman datahuman modelindexingindividualized medicinelipid metabolismmacrophagemolecular targeted therapiesmolnupiravirolfactory bulbpreventprospectivereceptorresponsesingle cell analysissingle-cell RNA sequencingsmall molecule inhibitorsystemic inflammatory responsetranscriptomevaccine developmentviral RNAwestern diet

项目摘要

项目成果

Chiara Giannarelli的其他基金

相似基金

相关文献

中文摘要
翻译
项目总结 冠状病毒病2019年(新冠肺炎)大流行,由严重急性呼吸系统综合症冠状病毒引起 2(SARS-CoV-2),仍然是一个全球卫生问题,尽管疫苗和 迫在眉睫的新抗病毒药物的前景,预计将成为地方性疾病。新冠肺炎与 动脉粥样硬化性心血管并发症,如急性冠脉综合征(ACS)、心肌梗死 (MI)和中风,这种风险在复苏后长达一年的时间内仍然很高,但潜在的机制 人们对此了解甚少。在初步工作中使用新冠肺炎患者的动脉粥样硬化组织进行尸检和 从新冠肺炎康复的受试者,以及体外SARS-CoV-2人体血管移植模型, 我们在人类斑块中鉴定了SARS-CoV-2病毒物质,这些病毒物质持续存在于康复患者的斑块中。 来自新冠肺炎。高水平人动脉粥样硬化斑块的单细胞RNA测序(ScRNAseq) Nrp1是SARS-CoV-2进入斑块巨噬细胞和泡沫细胞的受体。NRP-1 阻断阻止了SARS-CoV-2治疗后的人斑块中病毒物质的积累。这些数据 表明SARS-COV-2或其病毒成分可以在人体斑块中积聚,在那里它们会加剧 参与NRP-1的炎症和疾病进展。使用叙利亚金黄仓鼠模型, 忠实地模仿人类SARS-CoV2感染,我们发现病毒在心脏、肺和嗅觉中复制 感染仓鼠的鳞茎与ACE2的表达水平无关,支持替代作用 病毒进入的机制,如NRP-1。此外,该模型揭示了急性和持续的组织特异性。 几种组织中的炎症反应(即Nfkb1、IL6、IL1b)是由于循环中持续存在的 病毒清除后长达数周的非传染性病毒RNA碎片(VRNA)。基于这些令人兴奋的 初步数据,我们提出了两个独立的目标来研究SARS-CoV-2如何加重斑块炎症 和动脉粥样硬化,并确定急性和长期心血管事件风险增加的分子基础 在新冠肺炎患者中。在目标1中,我们将确定NRP-1在SARS-CoV-2诱导的动脉粥样硬化斑块中的作用 炎症和动脉粥样硬化进展。目标2将确定SARS-CoV-2 vRNA碎片的贡献 炎症和动脉粥样硬化。我们还将确定持久性vRNA对炎症和 病毒清除和新冠肺炎康复后的动脉粥样硬化。这些研究将解决重大差距。 了解SARS-CoV-2感染对斑块炎症和动脉粥样硬化的影响,并将应对 新冠肺炎患者血管紧张素转换酶活性增高的分子基础我们预见到这一信息将有助于 指导未来设计精确的治疗方法,以防止新冠肺炎患者的心血管结局。
英文摘要
PROJECT SUMMARY The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global health concern and despite the fast-track development of vaccines and the imminent prospective of new antiviral drugs, is expected to become endemic. COVID-19 is associated with atherosclerotic cardiovascular (CV) complications like acute coronary syndrome (ACS), Myocardial Infarction (MI) and stroke, a risk that remains high for up to one year following recovery, but the underlying mechanisms are poorly understood. In preliminary work using atherosclerotic tissue from COVID-19 patients at autopsy and subjects who recovered from COVID-19, along with an ex-vivo SARS-CoV-2 model of human vascular explants, we identified SARS-CoV-2 viral material in human plaques that persists in plaques of patients who recovered from COVID-19. Single cell RNA sequencing (scRNAseq) of human atherosclerotic plaques identified high levels of neuropilin-1 (NRP1), a receptor for SARS-CoV-2 entry, in plaque macrophages and foam cells. NRP-1 blockade abrogated the accumulation of viral material in SARS-CoV-2 treated human plaques. These data suggest that SARS-COV-2 or its viral components can accumulate in human plaques, where they exacerbate inflammation and disease progression by engaging NRP-1. Using the Syrian Golden hamster model, that faithfully mimics human SARS-CoV2 infection, we found that viral replication in the heart, lungs and olfactory bulb of infected hamsters did not correlate with expression levels of Ace2, supporting a role for alternative mechanisms of viral entry such as NRP-1. Moreover, this model revealed acute and sustained tissue-specific inflammatory responses (i.e. Nfkb1, Il6, Il1b) in several tissues due to the persistence in the circulation of noninfectious viral RNA debris (vRNA) for up to several weeks following viral clearance. Based on these exciting preliminary data, we propose two independent aims to study how SARS-CoV-2 aggravates plaque inflammation and atherosclerosis and to determine the molecular basis for the increased risk of acute and long-term CV events in COVID-19 patients. In Aim 1 we will identify the role of NRP-1 in SARS-CoV-2-induced atherosclerotic plaque inflammation and atherosclerosis progression. Aim 2 will identify the contribution of SARS-CoV-2 vRNA debris to inflammation and atherosclerosis. We will also determine the effect of persistent vRNA on inflammation and atherogenesis following viral clearance and recovery from COVID-19. These studies will address important gaps in knowledge on the effect of SARS-CoV-2 infection on plaque inflammation and atherosclerosis, and will tackle the molecular basis for the increased CV in patients with COVID-19. We foresee that this information will help guide the future design of precise therapies to prevent CV outcomes in patients with COVID-19.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Network-driven drug repurposing in cardiovascular disease: NDRA clinical trial planning
Dissecting the role of CD8+ T cells in atherosclerosis
Dissecting the role of CD8+ T cells in atherosclerosis
Dissecting the role of CD8+ T cells in atherosclerosis
国内基金
海外基金
ACE2/AGXT2信号轴在甲基异柳磷诱导斑马鱼神经发育异常过程中的作用机制研究
  • 批准号:
    JCZRLH202600625
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2026
  • 负责人:
  • 依托单位:
ACE2 Ser623磷酸化调控MED1促VSMCs功能损伤在移植血管重构中的作用及机制研究
  • 批准号:
    2026JJ50619
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2026
  • 负责人:
    翁春艳
  • 依托单位:
新型蝙蝠MERS簇冠状病毒HKU5的ACE2细胞受体识别及其分子机制研究
铁皮石斛通过肠道 ACE2 修复 Trp/GPR142 介 导“肠-胰岛 ”轴血糖调控功能的降糖机制研 究
  • 批准号:
    Y24H280055
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2024
  • 负责人:
    颜美秋
  • 依托单位: