Endothelial Cell and Cardiomyocyte Dysfunction in Children with Kawasaki disease-like SARS-CoV-2 Induced Immune Activation
Endothelial Cell and Cardiomyocyte Dysfunction in Children with Kawasaki disease-like SARS-CoV-2 Induced Immune Activation
批准号:
10165329
负责人:
JANE C BURNS
金额:
$72.77万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-01-01 至 2021-07-31
关键词:
2019-nCoVAcuteAddressAdministrative SupplementAffectAgeAneurysmAntibodiesAreaBiological AssayBiological MarkersBloodCOVID-19 pandemicCardiac MyocytesCardiovascular systemCellsChildChildhoodClinicalClinical DataClinical TreatmentClinical TrialsCoronary arteryDataDiagnosisEndothelial CellsEnzyme-Linked Immunosorbent AssayEthnic OriginEtiologyExposure toFeverFunctional disorderFundingGoalsHeart DiseasesHeart failureImmuneIn VitroIncubatedInfectionInflammasomeInflammationInflammatoryIntensive Care UnitsInterleukin-1Interleukin-6Intravenous ImmunoglobulinsLaboratoriesLung diseasesMediatingModelingMolecularMolecular ProfilingMucocutaneous Lymph Node SyndromeOutcomePathway interactionsPatientsPharmacotherapyPhenotypePlasmaPublicationsRNAReactionReportingResearchResistanceSamplingSerumShockSiteSteroidsSyndromeTNF geneTherapeuticTimeTubeVasculitisVirusWestern BlottingWestern EuropeWhole BloodWorkanakinracardiovascular healthcomparative effectiveness trialcytokinedrug efficacyefficacy testingimmune activationinflammatory markerneutrophilpatient populationpediatric patientsresponsetranscriptome sequencingtreatment guidelines
中文摘要
项目摘要
在COVID-19大流行之后,发热伴严重全身炎症和休克,称为儿科
炎症性多系统综合征(PIMS)已经发展成为儿童的新威胁。PIMS最初是
在西欧报告,在美国病例数迅速增加。PIMS的一个特点是,
心力衰竭导致休克,无明显肺部疾病。临床表现
在这些患者中,与获得性心脏病最常见的原因川崎病(KD)有许多共同特征
儿童疾病,其本身可表现为分布性休克,需要变力性和血管活性支持,
重症监护室一些PIMS患者要么是SARS-CoV-2 PCR阳性,要么已经发展成
抗SARS-CoV-2的抗体,表明PIMS是对先前暴露的免疫介导的反应
对病毒的反应奇怪的是,在病人被诊断患有PIMS的同时,
典型的KD在这些地区急剧增加。PIMS的出现是如此新颖,
快速发展,几乎没有与这些相关的出版物,治疗指南或临床试验
严重影响儿科患者。通过我们的30个参与KIDCARE的儿科中心网络,
由PCORI资助的治疗抵抗性KD的比较有效性试验,我们正在收集患者数据,
临床样本,以支持这里提出的工作。这份行政补充文件的目的是分析
人口统计学、临床和实验室数据以及使用患者细胞和血清的测定,
将使我们能够研究SARS-CoV-2感染,典型KD和PIMS之间的关系,并建立模型
针对PIMS的不同治疗策略。为实现这一目标,提出了三个具体目标。具体
目的1将描述和比较PIMS和典型KD的临床特征。人口统计学和临床数据以及
中性粒细胞对静脉注射免疫球蛋白(IVIG)的反应将在这两种疾病之间进行比较。
来自急性和亚急性PIMS和典型KD的血浆中的细胞因子谱和炎症标志物也将
被比较。具体目标2将阐明PIMS的分子特征,并与典型KD进行比较。我们将
使用RNA-seq、ELISA和蛋白质印迹分析来描绘与炎症相关的分子水平的变化
(e.g., TIFA、NFkβ、NLRP 3-炎性体、IL-1、IL-6、TNFα)和心血管健康(KLF 4、miR-483、ACE 2)
在内皮细胞和心肌细胞中。具体目标3将通过以下方式测试PIMS药物治疗的疗效:
比较静脉注射免疫球蛋白、类固醇和阿那白滞素对炎症通路的体外作用
用来自急性PIMS的血清处理的内皮细胞和心肌细胞中的心血管生物标志物
患者在治疗前在这个多PI补充调查小组的协同专业知识提供
了解PIMS的临床特征、分子基础和药物治疗疗效的独特机会
与KD相比。
英文摘要
Project Summary
In the wake of COVID-19 pandemic, fever with severe systemic inflammation and shock, known as Pediatric
Inflammatory Multisystem Syndrome (PIMS), has evolved as a new threat to children. PIMS was originally
reported in Western Europe and the number of cases is rapidly increasing in the U.S. A hallmark of PIMS has
been heart failure leading to shock and the absence of significant pulmonary disease. The clinical presentation
in these patients shares many features with Kawasaki disease (KD), the most common cause of acquired heart
disease in children, which itself can present with distributive shock requiring inotropic and vasoactive support in
the intensive care unit. Several PIMS patients are either SARS-CoV-2 PCR positive or have developed
antibodies against SARS-CoV-2, suggesting that PIMS is an immune-mediated reaction to antecedent exposure
to the virus. Curiously, at the same time that patients are being diagnosed with PIMS, the numbers of children
with typical KD has increased dramatically in these same regions. The emergence of PIMS is so new and so
rapidly evolving that there are literally no publications, treatment guidelines or clinical trials related to these
seriously affected pediatric patients. Through our network of 30 pediatric centers participating in KIDCARE, our
comparative effectiveness trial for treatment-resistant KD funded by PCORI, we are collecting patient data and
clinical samples to support the work proposed here. The goal of this administrative supplement is to analyze
demographic, clinical and laboratory data in conjunction with assays using patient cells and sera, which
will allow us to study the relationships among SARS-CoV-2 infection, typical KD, and PIMS and to model
different therapeutic strategies against PIMS. Three specific aims are proposed to achieve this goal. Specific
Aim 1 will profile and compare clinical features of PIMS and typical KD. Demographic and clinical data and the
neutrophil response to intravenous immunoglobulin (IVIG) will be compared between these two illnesses.
Cytokine profiles and inflammatory markers in plasma from acute and subacute PIMS and typical KD will also
be compared. Specific Aim 2 will elucidate molecular features of PIMS and compare with typical KD. We will
use RNA-seq, ELISA, and Western blot analyses to profile changes in levels of molecules related to inflammation
(e.g., TIFA, NFkβ, NLRP3-inflammasome, IL-1, IL-6, TNFα) and cardiovascular health (KLF4, miR-483, ACE2)
in endothelial cells and cardiomyocytes. Specific Aim 3 will test the efficacy of drug therapy for PIMS by
comparing the in vitro effects of intravenous immunoglobulin, steroids, and anakinra on inflammatory pathways
and cardiovascular biomarkers in endothelial cells and cardiomyocytes treated with sera from acute PIMS
patients prior to therapy. The synergistic expertise of the investigative teams in this multi-PI supplement provides
a unique opportunity to understand the clinical features, molecular basis, and efficacy of drug treatment of PIMS
as compared to KD.
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海外基金