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Mechanisms of childhood obesity underlying the susceptibility to multisystem inflammatory syndrome in children (MIS-C)

Mechanisms of childhood obesity underlying the susceptibility to multisystem inflammatory syndrome in children (MIS-C)
儿童肥胖导致儿童多系统炎症综合征易感性的机制(MIS-C)
批准号:
10641777
负责人:
Janet Chou
金额:
$44.25万
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:
2021-07-15 至 2024-06-30

项目摘要

项目成果

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中文摘要
翻译
项目概要/摘要 不可预测性是儿童多系统炎症综合征(MIS-C)的标志。MIS-C是一个 严重的儿科并发症SARS-CoV-2感染。MIS-C与COVID-19不同。它与 有心肺、自身免疫或血液疾病的患者。它可以发生在急性期, 可检测到SARS-CoV-2病毒,或在急性感染后数周的感染后阶段。温和 MIS-C的症状包括发热、皮疹和胃肠道症状,但可进展为血细胞减少, 凝血病、心肌功能障碍、冠状动脉瘤和/或休克。我们和其他人发现- C与儿童超重和肥胖有关,因此确定了超过3.8亿儿童有此风险 疾病超重和肥胖影响MIS-C发展的机制尚不清楚。 在全球所有儿童都能获得针对SARS-CoV-2的疫苗之前,他们仍将容易感染MIS-C。 我们的初步研究表明,MIS-C是一种高度炎症性疾病, 免疫细胞激活比COVID-19更快,特别是在超重和肥胖儿童中。超重和肥胖 患有MIS-C的儿童比正常体重的儿童有更多的T细胞淋巴细胞减少和T细胞活化, 表明患更严重疾病的风险增加。有害的遗传变异增加IFN和 炎症信号仅在MIS-C患者中发现,而不是严重的COVID-19。这是一 与成人中严重COVID-19相关的缺陷IFN信号传导的机械对应。我们的中央 一种假说认为,儿童超重和肥胖引发干扰素信号传导,从而增加T细胞 激活并最终导致MIS-C风险 目的1将阐明儿童超重和肥胖如何在MIS-C期间驱动免疫细胞功能障碍。 这项研究将验证儿童超重和肥胖与更多的 严重MIS-C,其特征在于过度的干扰素信号传导和T细胞活化。 目标2将确定MIS-C的机械风险因素。拟议中的研究将检验这一假设, 即使在没有感染的情况下,来自超重和肥胖儿童的循环免疫细胞也表现出 增加干扰素信号,促进T细胞活化。我们将制定一项战略,通过以下方式对MIS-C进行分层 将遗传筛查与体重指数测量相结合。 基于十多年的合作和MIS-C和/或肥胖儿童的独特队列, 我们的研究团队带来了MIS-C、宿主免疫、儿童肥胖和内分泌学方面的专业知识, 多组学该项目将产生超重和肥胖如何影响发展的因果见解, 和严重程度的MIS-C,目标是制定战略,人口仍然处于这种疾病的风险。
英文摘要
PROJECT SUMMARY/ABSTRACT Unpredictability is the hallmark of Multisystem Inflammatory Syndrome in Children (MIS-C). MIS-C is a severe pediatric complication of SARS-CoV-2 infection. MIS-C is distinct from COVID-19. It is not associated with pre-existing cardiopulmonary, autoimmune, or hematologic disorders. It can occur either during acute phase with detectable SARS-CoV-2 virus, or in the post-infectious period of several weeks after acute infection. Milder symptoms of MIS-C include fevers, rashes, and gastrointestinal symptoms, but can progress to cytopenias, coagulopathy, myocardial dysfunction, coronary aneurysms, and/or shock. We and others have found that MIS- C is associated with pediatric overweight and obesity, thereby identifying over 380 million children at risk for this disease. The mechanisms by which overweight and obesity influence the development of MIS-C are unknown. Until a vaccine against SARS-CoV-2 is globally available to all children, they will remain vulnerable to MIS-C. Our preliminary studies indicate that MIS-C is a highly inflammatory disease that incites more severe immune cell activation than COVID-19, particularly in overweight and obese children. Overweight and obese children with MIS-C had more T cell lymphopenia and T cell activation than their normal weight counterparts, suggesting an increased risk for more severe disease. Deleterious genetic variants increasing IFN and inflammatory signaling were exclusively found in patients with MIS-C, rather than severe COVID-19. This is a mechanistic counterpoint to defective IFN signaling associated with severe COVID-19 in adults. Our central hypothesis is that pediatric overweight and obesity prime interferon signaling, thereby increasing T cell activation and ultimately, the risk of MIS-C Aim 1 will elucidate how pediatric overweight and obesity drive immune cell dysfunction during MIS-C. The proposed studies will test the hypotheses that pediatric overweight and obesity are associated with more severe MIS-C, characterized by excessive interferon signaling and T cell activation. Aim 2 will identify mechanistic risk factors for MIS-C. The proposed studies will test the hypothesis that, even in the absence of infection, circulating immune cells from overweight and obese children exhibit an increased interferon signature that promotes T cell activation. We will develop a strategy for stratifying MIS-C by integrating genetic screening with measures of body mass index. Building on collaborations spanning over a decade and unique cohorts of children with MIS-C and/or obesity, our investigator team brings expertise in MIS-C, host immunity, pediatric obesity and endocrinology, and multiomics. This project will generate causal insights of how overweight and obesity influence the development and severity of MIS-C, with the goal of developing strategies for a population that remains at risk for this disease.
期刊论文(1)
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会议论文
DOI: 10.1002/ppul.25924
发表时间: 2022-07
期刊: PEDIATRIC PULMONOLOGY
影响因子: 3.1
作者: [Wobma, Holly, Perkins, Ryan, Bartnikas, Lisa, Dedeoglu, Fatma, Chou, Janet, Vleugels, Ruth Ann, Lo, Mindy S., Janssen, Erin, Henderson, Lauren A., Whangbo, Jennifer, Vargas, Sara O., Fishman, Martha, Krone, Katie A., Casey, Alicia]
通讯作者: Casey, Alicia
Mechanisms of childhood obesity underlying the susceptibility to multisystem inflammatory syndrome in children (MIS-C)
  • 批准号:
    10450145
  • 项目类别:
  • 资助金额:
    $44.25万
  • 财政年份:
    2021
  • 负责人:
    Janet Chou
  • 依托单位:
Mechanisms of pediatric overweight and obesity underlying susceptibility to multisystem inflammatory syndrome in children (MIS-C)
  • 批准号:
    10544668
  • 项目类别:
  • 资助金额:
    $10.22万
  • 财政年份:
    2021
  • 负责人:
    Janet Chou
  • 依托单位:
Mechanisms of childhood obesity underlying the susceptibility to multisystem inflammatory syndrome in children (MIS-C)
  • 批准号:
    10319758
  • 项目类别:
  • 资助金额:
    $44.25万
  • 财政年份:
    2021
  • 负责人:
    Janet Chou
  • 依托单位:
Molecular Basis of Allergic and Immunologic Disease
  • 批准号:
    10609496
  • 项目类别:
  • 资助金额:
    $75.62万
  • 财政年份:
    1986
  • 负责人:
    Janet Chou
  • 依托单位:
国内基金
海外基金
微米和纳米塑料作用下2019-nCoV抗病毒药物利巴韦林对河蚬的毒性作用机制
  • 批准号:
  • 项目类别:
    省市级项目
  • 资助金额:
    10.0万元
  • 批准年份:
    2021
  • 负责人:
    郭晓宇
  • 依托单位:
2019-nCoV感染导致人体淋巴细胞减低机制及其对机体免疫功能影响
  • 批准号:
    82030002
  • 项目类别:
    专项基金项目
  • 资助金额:
    135万元
  • 批准年份:
    2020
  • 负责人:
    曹彬
  • 依托单位:
基于人口流动大数据的新型冠状病毒(2019-nCoV)输出感染风险及接触网络传播模型研究
云南驯养野生动物中新型冠状病毒(2019-nCoV)溯源调查与验证
  • 批准号:
    --
  • 项目类别:
    --
  • 资助金额:
    140万元
  • 批准年份:
    2020
  • 负责人:
    夏雪山
  • 依托单位: